TW202328128A - Cdk7 inhibitors and methods of treating cancer - Google Patents

Cdk7 inhibitors and methods of treating cancer Download PDF

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TW202328128A
TW202328128A TW111135883A TW111135883A TW202328128A TW 202328128 A TW202328128 A TW 202328128A TW 111135883 A TW111135883 A TW 111135883A TW 111135883 A TW111135883 A TW 111135883A TW 202328128 A TW202328128 A TW 202328128A
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俊胡 張
萬隆 蔣
桑利 亞伯拉罕
凱文 杜安 班納
琴華 黃
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美商薩諾管理公司
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Abstract

Compounds of Formula (I) and pharmaceutically active salts thereof are provided, where the variables in Formula (I) are described herein. Such compounds and salts are CDK7 inhibitors that are useful for treating conditions characterized by excessive cellular proliferation, such as cancer and tumors.

Description

CDK7抑制劑及治療癌症之方法CDK7 inhibitors and methods for treating cancer

本申請案大致上係關於作為CDK7抑制劑的化合物、及使用其治療特徵為過度細胞增生之病況（諸如癌症及腫瘤）的方法。The present application relates generally to compounds that are inhibitors of CDK7, and methods of using the same to treat conditions characterized by excessive cellular proliferation, such as cancer and tumors.

週期蛋白依賴性激酶7 (Cyclin-dependent kinase 7, CDK7)係週期蛋白依賴性蛋白激酶(CDK)家族中之蛋白。其與涉及T迴路磷酸化及驅動細胞週期進展之週期蛋白H及MAT1形成複合物。CDK7亦作為轉錄因子TFIIH之組分涉及轉錄之調控。參見Sava, G.P. et al, “CDK7 Inhibitors as Anticancer Drugs,” Cancer and Metastasis Reviews(2020) 39:805-823。 Cyclin-dependent kinase 7 (CDK7) is a protein in the cyclin-dependent kinase (CDK) family. It forms a complex with cyclin H and MAT1, which are involved in T-loop phosphorylation and driving cell cycle progression. CDK7 is also involved in the regulation of transcription as a component of the transcription factor TFIIH. See Sava, GP et al, "CDK7 Inhibitors as Anticancer Drugs," Cancer and Metastasis Reviews (2020) 39:805-823.

已評估抑制CDK7之多種具各種化學結構之化合物之治療癌症及/或腫瘤之能力。例如，表1繪示若干選擇性CDK7抑制劑，其已進展至涉及患有晚期實體惡性腫瘤患者的第I/II期臨床試驗： 表 1 CDK7 抑制劑 結構 沙美西利(Samuraciclib) (ICEC0942) 美沃西利(Mevociclib) (SY-1365) LY3405105 Various compounds of various chemical structures that inhibit CDK7 have been evaluated for their ability to treat cancer and/or tumors. For example, Table 1 depicts several selective CDK7 inhibitors that have progressed to Phase I/II clinical trials involving patients with advanced solid malignancies: Table 1 CDK7 inhibitor structure Samuraciclib (ICEC0942) Mevociclib (SY-1365) LY3405105

多種化合物之臨床進展代表CDK7抑制劑發展中的里程碑。然而，仍有抑制CDK7活性之改良化合物之需要。The clinical progress of multiple compounds represents a milestone in the development of CDK7 inhibitors. However, there remains a need for improved compounds that inhibit CDK7 activity.

各種實施例提供式(I)化合物及其使用之方法。Various embodiments provide compounds of formula (I) and methods of their use.

一實施例提供式(I)之化合物： (I) 或其醫藥上可接受之鹽，其中： R 1及R 2獨立地係氫、鹵素、CN、烷基、烷氧基、鹵烷基、羥烷基、環烷基、NHR 5a、或NR 5aR 5b； R 3係經取代或未經取代之C 3-C 8環烷基、或C 3-C 8雜環基，其中該經取代之C 3-C 8環烷基、或C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基、烷氧基、鹵烷基、環烷基、雜環基、NHR 5a、NR 5aR 5b、或OR 6之基團所取代； R 4係鹵素、CN、烷基、環烷基、-NR 7R 8、OR 6、-CO 2R 6、或-C(O)-NR 7R 8； 各R 5a、R 5b、及R 6獨立地係氫、烷基、鹵烷基、或環烷基； R 7及R 8獨立地係氫、經取代或未經取代之烷基、或經取代或未經取代之環烷基；其中該經取代之烷基或經取代之環烷基係經1至3個獨立地選自鹵素、OR 6、CN、烷基、NHR 5a、或NR 5aR 5b所取代；或 R 7及R 8連同其所連接之N一起形成未經取代或經取代的C 3-C 8雜環基，其中該經取代之C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基、烷氧基、鹵烷基、環烷基、雜環基、NHR 5a、NR 5aR 5b或OR 6之基團所取代； X係N或CR 9； Q 1係C或N； Q 2係CH或N； Q 3係CH、N、或NH；前提係當Q 1係N時，則Q 3係N； R 9係氫、 、 、或 ； 各R 10獨立地係氫、烷基、鹵烷基、或環烷基； Y及Z獨立地係N或CH，及 各n獨立地係0、1、2、3、或4。 One embodiment provides compounds of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , Or NR 5a R 5b ; R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl, wherein the substituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl is one or more independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 R 4 is halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , -CO 2 R 6 , or -C(O)-NR 7 R 8 ; each R 5a , R 5b , and R 6 are independently hydrogen, alkyl, haloalkyl, or cycloalkyl; R 7 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted Substituted cycloalkyl; wherein the substituted alkyl or substituted cycloalkyl is substituted by 1 to 3 independently selected from halogen, OR 6 , CN, alkyl, NHR 5a , or NR 5a R 5b ; or R 7 and R 8 together with the N to which they are attached form an unsubstituted or substituted C 3 -C 8 heterocyclyl, wherein the substituted C 3 -C 8 heterocyclyl is via one or more Substituted by a group independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b or OR 6 ; X is N or CR 9 ; Q 1 C or N; Q 2 is CH or N; Q 3 is CH, N, or NH; the premise is that when Q 1 is N, then Q 3 is N; R 9 is hydrogen, , ,or each R 10 is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; Y and Z are independently N or CH, and each n is independently 0, 1, 2, 3, or 4.

另一實施例提供一種醫藥組成物，其包含本文所述之化合物、或其醫藥上之活性鹽、及醫藥上可接受之載劑、稀釋劑、賦形劑、或其組合。Another embodiment provides a pharmaceutical composition, which comprises the compound described herein, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

另一實施例提供一種用於治療癌症或腫瘤之方法，其包含對患有癌症或腫瘤之對象投予有效量之本文所述之化合物、或其醫藥上活性之鹽、或本文所述之醫藥組成物。Another embodiment provides a method for treating cancer or tumor, which comprises administering an effective amount of a compound described herein, or a pharmaceutically active salt thereof, or a drug described herein to a subject suffering from cancer or tumor Composition.

以下更詳細地描述這些及其他實施例。These and other embodiments are described in more detail below.

以引用方式併入任何優先權申請案中Incorporated by reference into any priority application

本申請案主張於2021年09月23日申請之美國臨時專利申請案第63/261,546號之優先權，該申請案特此以引用方式全文併入本文中。This application claims priority to U.S. Provisional Patent Application No. 63/261,546, filed September 23, 2021, which application is hereby incorporated by reference in its entirety.

週期蛋白依賴性激酶(Cyclin-dependent kinase, CDK)係激酶之主要類別，且在癌細胞增生及失控之致癌性轉錄中係重要的。CDK7結合至週期蛋白H及MATI，以形成藉由磷酸化其他涉及細胞週期調控之CDK來執行其功能之三聚週期蛋白活化激酶(cyclin-activating kinase, CAK)。此等複合物控制細胞週期中兩個接續階段之間的特定轉變。CDK7牽涉在細胞週期之時間控制及轉錄活性兩者中。CDK7藉由磷酸化RNA聚合酶II (RNAPII)之Rbp1次單元牽涉在轉錄起始程序中。未受控細胞增生及失控之轉錄係癌症標誌。靶向CDK7選擇性可藉由同時抑制活性轉錄及細胞週期進展而提供優點。因此，CDK7對於癌症治療係有前景之目標，尤其對於侵襲性且難以治療之癌症。 定義 Cyclin-dependent kinases (CDKs) are a major class of kinases and are important in cancer cell proliferation and uncontrolled oncogenic transcription. CDK7 binds to cyclin H and MATI to form a trimeric cyclin-activating kinase (CAK) that performs its function by phosphorylating other CDKs involved in cell cycle regulation. These complexes control specific transitions between two successive phases in the cell cycle. CDK7 is involved in both temporal control of the cell cycle and transcriptional activity. CDK7 is involved in the transcription initiation process by phosphorylating the Rbp1 subunit of RNA polymerase II (RNAPII). Uncontrolled cell proliferation and unregulated transcription are hallmarks of cancer. Targeting CDK7 selectively may provide advantages by simultaneously inhibiting active transcription and cell cycle progression. Therefore, CDK7 is a promising target for cancer therapy, especially for aggressive and difficult-to-treat cancers. definition

除非另外定義，否則本文中所使用之所有技術及科學用語具有與所屬技術領域中具有通常知識者所共同理解的相同含義。除非另有說明，本文所引用之所有專利、申請案、公開申請案、及其他出版物之全文均以引用之方式併入本文中。若在本文中之用語具有複數個定義，除非另有說明，否則以此節之定義為主。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If a term in this article has multiple definitions, unless otherwise stated, the definition in this section prevails.

每當基團經描述為「可選地經取代的(optionally substituted)」時，該基團可未經取代或經一或多個指示取代基取代。同樣，當基團經描述為「未經取代或經取代(unsubstituted or substituted)」時，若經取代，則（多個）取代基可選自一或多個指示的取代基。如果沒有指示取代基，則代表所指示之「可選地經取代(optionally substituted)」或「經取代(substituted)」基團可經一或多個個別地且獨立地選自下列之基團所取代：烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳基(烷基)、環烷基(烷基)、雜芳基(烷基)、雜環基(烷基)、羥基、烷氧基、醯基、氰基、鹵素、硫羰基、O-胺甲醯基、N-胺甲醯基、O-胺硫甲醯基、N-胺硫甲醯基、C-醯胺基、N-醯胺基、S-磺醯胺基、N-磺醯胺基、C-羧基、O-羧基、硝基、次磺醯基(sulfenyl)、亞磺醯基、磺醯基、鹵烷基、鹵烷氧基、胺基、經單取代胺基、經二取代胺基、經單取代胺(烷基)、及經二取代胺(烷基)。Whenever a group is described as being "optionally substituted," that group can be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" group may be replaced by one or more groups individually and independently selected from the following groups Substitution: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alk base), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-aminothioformyl, N-aminothioformyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, nitro, sulfenyl ( sulfenyl), sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino, disubstituted amino, monosubstituted amine (alkyl), and disubstituted amine (alkyl).

如本文中所使用，「C a至C b」中之「a」及「b」係整數，其係指基團中之碳原子數目。所指示的基團可包括性(inclusive)的含有「a」至「b」個碳原子。因此，「C 1至C 4烷基」係指所有具有1至4個碳之烷基，亦即CH 3-、CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、CH 3CH 2CH(CH 3)-、及(CH 3) 3C-。如果未指定「a」及「b」，則假定此等定義中描述之最寬範圍。 As used herein, "a" and "b" in "C a to C b " are integers which refer to the number of carbon atoms in the group. Indicated groups may be inclusive and contain "a" to "b" carbon atoms. Thus, "C 1 to C 4 alkyl" refers to all alkyl groups having 1 to 4 carbons, ie CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH -, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, and (CH 3 ) 3 C-. If "a" and "b" are not specified, the broadest range described in these definitions is assumed.

如果將兩個「R」基團描述為「一起(taken together)」，則該等R基團及其等所附接之原子可形成環烷基、環烯基、芳基、雜芳基、或雜環。例如但不限於，如果將NR aR b基團之R a及R b描述為「一起」，則代表其等係彼此共價鍵結以形成環： If two "R" groups are described as being "taken together," the R groups and the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycles. For example, without limitation, if R a and R b of an NR a R b group are described as "together", it means that they are covalently bonded to each other to form a ring:

如本文中所使用，用語「烷基(alkyl)」係指完全飽和之脂族烴基。烷基部份可係支鏈或直鏈。支鏈烷基之實例包括但不限於異丙基、二級丁基、三級丁基、及類似者。直鏈烷基之實例包括但不限於甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、及類似者。烷基可具有1至30個碳原子（每當在本文中出現時，數值範圍諸如「1至30」係指給定範圍中之每個整數；例如，「1至30個碳原子」意指烷基可由1個碳原子、2個碳原子、3個碳原子、等、直至並且包括30個碳原子所組成，雖然本定義亦涵蓋未指定數值範圍之用語「烷基」之出現）。烷基亦可係具有1至12個碳原子之中等大小烷基。烷基亦可係具有1至6個碳原子之低級烷基。烷基可係經取代的或未經取代的。As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, secondary butyl, tertiary butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have from 1 to 30 carbon atoms (whenever appearing herein, a numerical range such as "1 to 30" refers to each integer in the given range; for example, "1 to 30 carbon atoms" means An alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers occurrences of the term "alkyl" without specifying a numerical range). The alkyl group can also be a medium size alkyl group having 1 to 12 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups can be substituted or unsubstituted.

如本文中所使用，用語「伸烷基(alkylene)」係指二價完全飽和之直鏈脂族烴基。伸烷基之實例包括但不限於亞甲基、伸乙基、伸丙基、伸丁基、伸戊基、伸己基、伸庚基、及伸辛基。伸烷基可由 代表，後面接著碳原子數目，然後再接著「*」。例如， 代表伸乙基。伸烷基具有1至30個碳原子（每當在本文中出現時，數值範圍諸如「1至30」係指給定範圍中之每個整數；例如，「1至30個碳原子」意指伸烷基可由1個碳原子、2個碳原子、3個碳原子、等、直至並且包括30個碳原子所組成，雖然本定義亦涵蓋未指定數值範圍之用語「烷基」之出現）。伸烷基亦可係具有1至12個碳原子之中等大小烷基。伸烷基亦可係具有1至4個碳原子之低級烷基。伸烷基可係經取代的或未經取代的。例如，低級伸烷基可藉由置換該低級伸烷基之一或多個氫及/或藉由用C 3-6單環環烷基（例如， ）取代同一個碳上的兩個氫來取代。 As used herein, the term "alkylene" refers to a divalent fully saturated straight-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylenyl, butyl, pentylene, hexylene, heptyl, and octyl. Alkylene can be given by represents, followed by the number of carbon atoms, and then followed by "*". For example, Represents ethylenyl. The alkylene group has 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as "1 to 30" means each integer in the given range; for example, "1 to 30 carbon atoms" means An alkylene group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers occurrences of the term "alkyl" without specifying a numerical range). The alkylene group can also be a medium size alkyl group having 1 to 12 carbon atoms. The alkylene group can also be a lower alkyl group having 1 to 4 carbon atoms. Alkylene groups can be substituted or unsubstituted. For example, a lower alkylene can be obtained by replacing one or more hydrogens of the lower alkylene and/or by replacing one or more hydrogens of the lower alkylene with a C 3-6 monocyclic cycloalkyl (for example, ) to replace two hydrogens on the same carbon.

本文中所使用之用語「烯基(alkenyl)」係指含有（多個）碳雙鍵之二至二十個碳原子的單價直鏈或支鏈基團，包括但不限於1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、及類似者。烯基可係未經取代或經取代的。The term "alkenyl" as used herein refers to a monovalent linear or branched chain group of two to twenty carbon atoms containing a carbon double bond(s), including but not limited to 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups can be unsubstituted or substituted.

本文中所使用之用語「炔基(alkynyl)」係指含有（多個）碳三鍵之二至二十個碳原子的單價直鏈或支鏈基團，包括但不限於1-丙炔基、1-丁炔基、2-丁炔基、及類似者。炔基可係未經取代或經取代的。As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched chain group containing two to twenty carbon atoms containing a carbon triple bond(s), including but not limited to 1-propynyl , 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be unsubstituted or substituted.

如本文中所使用，「環烷基(cycloalkyl)」係指完全飽和（無雙鍵或三鍵）單環或多環（諸如雙環）烴環系統。當由二或更多個環構成時，環可以稠合、架橋或螺形方式接合在一起。如本文中所使用，用語「稠合(fused)」係指共用二個原子及一個鍵結的二個環。如本文中所使用，用語「架橋環烷基(bridged cycloalkyl)」係指其中環烷基含有連接非相鄰原子的一或多個原子的鍵聯的化合物。如本文中所使用，用語「螺(spiro)」係指兩個環共用一個原子且該兩個環非以架橋接合。環烷基可以在（多個）環中含有3至30個原子、在（多個）環中含有3至20個原子、在（多個）環中含有3至10個原子、在（多個）環中含有3至8個原子、或在（多個）環中含有3至6個原子。環烷基可係未經取代或經取代的。單環烷基之實例包括但絕不限於環丙基、環丁基、環戊基、環己基、環庚基、及環辛基。稠合環烷基之實例係十氫萘基、十二氫-1H-萉基、及十四氫萘基；橋接環烷基之實例係雙環[1.1.1]戊基、金剛烷基(adamantanyl)、及降莰烷基(norbornanyl)；及螺環烷基之實例包括螺[3.3]庚烷、及螺[4.5]癸烷。As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bond) monocyclic or polycyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged cycloalkyl" refers to a compound in which the cycloalkyl contains a linkage to one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-onyl, and tetrahydronaphthyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl ), and norbornanyl (norbornanyl); and examples of spirocycloalkyl include spiro [3.3] heptane, and spiro [4.5] decane.

如本文中所使用，「環烯基(cycloalkenyl)」係指在至少一個環中含有一或多個雙鍵之單環或多環（諸如雙環）烴環系統；但如果有超過一個雙鍵，雙鍵不可形成遍及所有環之完全非定域π-電子系統（否則基團將為如在本文中定義之「芳基(aryl)」）。例如，環烯基可在（多個）環中含有3至10個原子、在（多個）環中含有3至8個原子、或在（多個）環中含有3至6個原子。當包含二或更多個環時，環可用稠合、架橋或螺合方式連接在一起。環烯基可係未經取代或經取代的。As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic (such as bicyclic) hydrocarbon ring system containing one or more double bonds in at least one ring; but if there is more than one double bond, The double bond cannot form a fully delocalized π-electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). For example, a cycloalkenyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). When two or more rings are included, the rings can be joined together by fused, bridged or spiro-connected. Cycloalkenyl groups can be unsubstituted or substituted.

如本文中所使用，「芳基(aryl)」係指碳環（全碳）單環或多環（諸如雙環）芳環系統（包括兩個碳環共用化學鍵之稠合環系統），其在所有環中具有完全離域的π-電子系統。芳基中的碳原子數目可有所變化。例如，芳基可係C 6-C 14芳基、C 6-C 10芳基、或C 6芳基。芳基的實例包括但不限於苯、萘、及薁。芳基可係經取代或未經取代的。 As used herein, "aryl" means a carbocyclic (full carbon) monocyclic or polycyclic (such as bicyclic) aromatic ring system (including a fused ring system in which two carbocyclic rings share a chemical bond), which in All rings have fully delocalized π-electron systems. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

如本文中所使用，「雜芳基(heteroaryl)」係指單環或多環（諸如雙環）芳環系統（具有完全離域的π-電子系統之環系統），其含有一或多個雜原子（例如，1、2、或3個雜原子），亦即除碳之外的元素，包括但不限於氮、氧、及硫。雜芳基之（多個）環中的原子數目可有所變化。例如，雜芳基可在（多個）環中含有4至14個原子、在（多個）環中含有5至10個原子、或在（多個）環中含有5至6個原子，諸如九個碳原子及一個雜原子；八個碳原子及二個雜原子；七個碳原子及三個雜原子；八個碳原子及一個雜原子；七個碳原子及二個雜原子；六個碳原子及三個雜原子；五個碳原子及四個雜原子；五個碳原子及一個雜原子；四個碳原子及二個雜原子；三個碳原子及三個雜原子；四個碳原子及一個雜原子；三個碳原子及二個雜原子；或二個碳原子及三個雜原子。此外，用語「雜芳基(heteroaryl)」包括稠合環系統，其中兩個環（諸如至少一個芳基環及至少一個雜芳基環或至少兩個雜芳基環）共用至少一個化學鍵。雜芳基環之實例包括但不限於呋喃、呋呫、噻吩、苯并噻吩、呔 、吡咯、 唑、苯并 唑、1,2,3- 二唑、1,2,4- 二唑、噻唑、1,2,3-噻二唑、1,2,4-噻二唑、苯并噻唑、咪唑、苯并咪唑、吲哚、吲唑、吡唑、苯并吡唑、異 唑、苯并異 唑、異噻唑、***、苯并***、噻二唑、四唑、吡啶、嗒 、嘧啶、吡 、嘌呤、喋啶、喹啉、異喹啉、喹唑啉、喹 啉、 啉、及三 。雜芳基可係經取代或未經取代的。 As used herein, "heteroaryl" refers to a monocyclic or polycyclic (such as bicyclic) aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroaryl Atoms (eg, 1, 2, or 3 heteroatoms), ie, elements other than carbon, include, but are not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), such as Nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atom and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms atom and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furan, thiophene, benzothiophene, thiophene, , pyrrole, Azole, benzo Azole, 1,2,3- Oxadiazole, 1,2,4- Oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, iso azoles, benziso Azole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridine , pyrimidine, pyrimidine , purine, pteridine, quinoline, isoquinoline, quinazoline, quinoline phylloline, phylloline, and three . Heteroaryl groups can be substituted or unsubstituted.

所屬技術領域中具有通常知識者理解，在以下部分之稠合「A」環中之部分環指示「A」環係芳族： Those of ordinary skill in the art understand that partial rings in fused "A" rings in the following moieties indicate that the "A" ring system is aromatic:

例如，當Q 1、Q 2、及Q 3中任一或多者係氮，上述部分係雜芳基。類似地，當所有Q 1、Q 2、及Q 3都係碳，上述部分係芳基。 For example, when any one or more of Q 1 , Q 2 , and Q 3 are nitrogen, the above moieties are heteroaryl. Similarly, when all of Q 1 , Q 2 , and Q 3 are carbon, the aforementioned moieties are aryl.

如本文中所使用，「雜環基(heterocyclyl)」或「雜脂環基(heteroalicyclyl)」係指三、四、五、六、七、八、九、十到至多18員單環、雙環、及三環環系統，其中碳原子與1至5個雜原子一起構成該環系統。雜環可以可選地含有一或多個以這種方式定位之不飽和鍵，然而，完全離域的π電子系統不會發生在所有環中。（多個）雜原子係除碳以外的元素，包括但不限於氧、硫（例如-S-、-S(=O)-、或-S(=O) 2-）、及氮（例如-N=、-NH-、或-N(烷基)-）。雜環可進一步含有一或多個羰基或硫羰基官能性，以使定義包括側氧基系統及硫基系統，諸如內醯胺、內酯、環狀醯亞胺、環狀硫醯亞胺、及環狀胺甲酸酯。當由二或更多個環構成時，環可以稠合、架橋或螺形方式接合在一起。如本文中所使用，用語「稠合(fused)」係指共用二個原子及一個鍵結的二個環。如本文中所使用，用語「架橋雜環基(bridged heterocyclyl)」或「架橋雜脂環基(bridged heteroalicyclyl)」係指其中雜環基或雜脂環基含有連接非相鄰原子之一或多個原子的鍵聯之化合物。如本文中所使用，用語「螺(spiro)」係指兩個環共用一個原子且該兩個環非以架橋接合。雜環基及雜脂環基可以在（多個）環中含有3至30個原子、在（多個）環中含有3至20個原子、在（多個）環中含有3至10個原子、在（多個）環中含有3至8個原子、在（多個）環中含有3至6個原子。例如，五個碳原子及一個雜原子；四個碳原子及二個雜原子；三個碳原子及三個雜原子；四個碳原子及一個雜原子；三個碳原子及二個雜原子；二個碳原子及三個雜原子；一個碳原子及四個雜原子；三個碳原子及一個雜原子；或二個碳原子及一個雜原子。此外，雜脂環中之任何氮可為四級銨化的。雜環基或雜脂環基團可係未經取代的或經取代的。此類「雜環基(heterocyclyl)」或「雜脂環基(heteroalicyclyl)」之實例包括但不限於1,3-戴奧辛、1,3-二 烷、1,4-二 烷、1,2-二氧雜環戊烷、1,3-二氧雜環戊烷、1,4-二氧雜環戊烷、1,3-氧硫雜環己烷(1,3-oxathiane)、1,4-氧硫雜環己二烯(1,4-oxathiin)、1,3-氧硫雜環戊烷(1,3-oxathiolane)、1,3-二硫雜環戊烯(1,3-dithiole)、1,3-二硫雜環戊烷(1,3-dithiolane)、1,4-氧硫雜環己烷、四氫-1,4-噻 、2H-1,2- 、馬來醯亞胺、琥珀醯亞胺、巴比妥酸、硫巴比妥酸、二氧哌 、乙內醯脲、二氫尿嘧啶、三 烷、六氫-1,3,5-三 、咪唑啉、咪唑啶、異 唑啉、異 唑啶、 唑啉、 唑啶、 唑啶酮、噻唑啉、噻唑啶、嗎啉、環氧乙烷、哌啶N-氧化物、哌啶、哌 、吡咯啶、氮 、吡咯啶酮、吡咯啶二酮、4-哌啶酮、吡唑啉、吡唑啶、2-氧吡咯啶、四氫吡喃、4H-吡喃、四氫噻喃、硫嗎啉、硫嗎啉亞碸、硫嗎啉碸、及其苯并稠合類似物（例如，苯并咪唑啶酮、四氫喹啉、及/或3,4-亞甲基二氧基苯基）。螺雜環基之實例包括2-氮雜螺[3.3]庚烷、2-氧雜螺[3.3]庚烷、2-氧雜-6-氮雜螺[3.3]庚烷、2,6-二氮雜螺[3.3]庚烷、2-氧雜螺[3.4]辛烷、及2-氮雜螺[3.4]辛烷。 As used herein, "heterocyclyl" or "heteroalicyclyl" refers to three, four, five, six, seven, eight, nine, ten to up to 18 membered monocyclic, bicyclic, and tricyclic ring systems, wherein the carbon atoms form the ring system together with 1 to 5 heteroatoms. Heterocycles may optionally contain one or more unsaturated bonds positioned in this manner, however, fully delocalized π-electron systems do not occur in all rings. Heteroatom(s) are elements other than carbon, including but not limited to oxygen, sulfur (eg -S-, -S(=O)-, or -S(=O) 2 -), and nitrogen (eg - N=, -NH-, or -N(alkyl)-). The heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities such that the definition includes pendant oxygen systems as well as thio systems such as lactamides, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a heterocyclyl or heteroalicyclyl group in which one or more of the non-adjacent atoms are linked. A bonded compound of atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. Heterocyclic and heteroalicyclic groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s) , 3 to 8 atoms in the ring(s), 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; Two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. In addition, any nitrogen in the heteroalicyclic ring may be quaternary ammonized. A heterocyclyl or heteroalicyclic group can be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" include, but are not limited to, 1,3-dioxin, 1,3-di Alkane, 1,4-bis alkane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiolane (1,3- oxathiane), 1,4-oxathiin (1,4-oxathiin), 1,3-oxathiolane (1,3-oxathiolane), 1,3-dithiolane (1,3-dithiole), 1,3-dithiolane (1,3-dithiolane), 1,4-oxathiolane, tetrahydro-1,4-thiolane , 2H-1,2- , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopane , hydantoin, dihydrouracil, three Alkane, hexahydro-1,3,5-tri , imidazoline, imidazolidine, iso oxazoline, iso Azolidine, oxazoline, Azolidine, Pazolidone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperidine , pyrrolidine, nitrogen , pyrrolidone, pyrrolidinone, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, sulfur Morpholinoxine, thiomorpholino, and benzo-fused analogs thereof (eg, benzimidazolidinone, tetrahydroquinoline, and/or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-di Azaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

如本文中所使用，「芳烷基(aralkyl)」及「芳基(烷基) (aryl(alkyl))」係指經由低級伸烷基連接作為取代基之芳基。芳烷基之低級伸烷基及芳基可係經取代的或未經取代的。實例包括但不限於苄基、2-苯基烷基、3-苯基烷基、及萘基烷基。As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group as a substituent attached via a lower alkylene group. The lower alkylene and aryl groups of the aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

如本文中所使用，「雜芳烷基(heteroaralkyl)」及「雜芳基(烷基) (heteroaryl(alkyl))」係指經由低級伸烷基連接作為取代基之雜芳基。雜芳烷基之低級伸烷基及雜芳基可係經取代的或未經取代的。實例包括但不限於2-噻吩基烷基、3-噻吩基烷基、呋喃基烷基、噻吩基烷基、吡咯基烷基、吡啶基烷基、異 唑基烷基、及咪唑基烷基、及其苯并稠合類似物。 As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group as a substituent linked via a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaralkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, iso Azolylalkyl, and imidazolylalkyl, and benzofused analogs thereof.

「雜脂環基(烷基) (heteroalicyclyl(alkyl))」及「雜環基(烷基) (heterocyclyl(alkyl))」係指經由低級伸烷基連接作為取代基之雜環基或雜脂環基。(雜脂環基)烷基之低級伸烷基及雜環基可係經取代的或未經取代的。實例包括但不限於四氫-2H-哌喃-4-基(甲基)、哌啶-4-基(乙基)、哌啶-4-基(丙基)、四氫-2H-噻喃-4-基(甲基)及1,3-噻嗪-4-基(甲基)(1,3-thiazinan-4-yl(methyl))。"Heteroalicyclyl (alkyl)" and "heterocyclyl (alkyl)" refer to a heterocyclic group or a heteroaliphatic group linked via a lower alkylene group as a substituent Ring base. The lower alkylene and heterocyclyl of (heteroalicyclic)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl (methyl) and 1,3-thiazinan-4-yl (methyl) (1,3-thiazinan-4-yl (methyl)).

如本文中所使用，用語「羥基(hydroxy)」係指–OH基團。As used herein, the term "hydroxy" refers to an -OH group.

如本文中所使用，「烷氧基(alkoxy)」係指式–OR，其中R係本文中所定義之烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。烷氧基之非限制性列表係甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(異丙氧基)、正丁氧基、異丁氧基、二級丁氧基、三級丁氧基、苯氧基、及苄醯氧基。烷氧基可係經取代或未經取代的。As used herein, "alkoxy" refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl as defined herein radical, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy group, tertiary butoxy, phenoxy, and benzyloxy. Alkoxy groups can be substituted or unsubstituted.

如本文中所使用，「醯基(acyl)」係指經由羰基連接作為取代基之氫、烷基、烯基、炔基、芳基、雜芳基、雜環基、芳基(烷基)、雜芳基(烷基)、及雜環基(烷基)。實例包括甲醯基、乙醯基、丙醯基、苄醯基、及丙烯醯基。醯基可係經取代或未經取代的。As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl) attached as a substituent through a carbonyl group , heteroaryl (alkyl), and heterocyclyl (alkyl). Examples include formyl, acetyl, propionyl, benzyl, and acryl. Acyl groups can be substituted or unsubstituted.

「氰基(cyano)」係指「-CN」基團。"cyano" refers to a "-CN" group.

如本文中所使用之用語「鹵素原子(halogen atom)」或「鹵素(halogen)」意指元素周期表第7欄之任一種放射穩定原子，諸如氟、氯、溴、及碘。The term "halogen atom" or "halogen" as used herein means any radioactive stable atom in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine, and iodine.

「硫羰基(thiocarbonyl)」係指「-C(=S)R」基團，其中R可與關於O-羧基所定義者相同。硫羰基可係經取代或未經取代的。"thiocarbonyl" refers to a "-C(=S)R" group, where R may be the same as defined for O-carboxy. Thiocarbonyl groups can be substituted or unsubstituted.

「O-胺甲醯基(O-carbamyl)」係指「-OC(=O)N(R AR B)」基團，其中R A及R B可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。O-胺甲醯基可係經取代的或未經取代的。 "O-carbamyl" refers to the "-OC(=O)N( RA R B )" group, where R A and R B can be independently hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl). An O-aminoformyl group can be substituted or unsubstituted.

「N-胺甲醯基(N-carbamyl)」係指「ROC(=O)N(R A)-」基團，其中R及R A可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N-胺甲醯基可係經取代的或未經取代的。 "N-carbamyl" refers to the "ROC(=O)N( RA )-" group, where R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The N-aminoformyl group can be substituted or unsubstituted.

「O-硫胺甲醯基(O-thiocarbamyl)」係指「-OC(=S)-N(R AR B)」基團，其中R A及R B可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。O-胺硫甲醯基可係經取代的或未經取代的。 "O-thiocarbamyl (O-thiocarbamyl)" refers to the "-OC(=S)-N( RA R B )" group, wherein R A and R B can be independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or hetero Cyclic (alkyl). The O-thiocarbamoyl group can be substituted or unsubstituted.

「N-硫胺甲醯基(N-thiocarbamyl)」係指「ROC(=S)N(R A)-」基團，其中R及R A可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N-胺硫甲醯基可係經取代的或未經取代的。 "N-thiocarbamyl (N-thiocarbamyl)" refers to the group "ROC(=S)N( RA )-", wherein R and RA can be independently hydrogen, alkyl, alkenyl, alkyne radical, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl base). N-thiocarbamoyl can be substituted or unsubstituted.

「C-醯胺基(C-amido)」係指「-C(=O)N(R AR B)」基團，其中R A及R B可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。C-醯胺基可係經取代的或未經取代的。 "C-amido" refers to a "-C(=O)N( RA R B )" group, wherein R A and R B can be independently hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl( alkyl). A C-amido group can be substituted or unsubstituted.

「N-醯胺基(N-amido)」係指「RC(=O)N(R A)-」基團，其中R及R A可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N-醯胺基可係經取代的或未經取代的。 "N-amido" refers to the group "RC(=O)N( RA )-", wherein R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) . N-amido groups can be substituted or unsubstituted.

「S-磺醯胺基(S-sulfonamido)」係指「-SO 2N(R AR B)」基團，其中R A及R B可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。S-磺醯胺基可係經取代的或未經取代的。 "S-sulfonamido (S-sulfonamido)" refers to the "-SO 2 N( RA R B )" group, where R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The S-sulfonylamino group can be substituted or unsubstituted.

「N-磺醯胺基(N-sulfonamido)」係指「RSO 2N(R A)-」基團，其中R及R A可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N-磺醯胺基可係經取代的或未經取代的。 "N-sulfonamido (N-sulfonamido)" refers to the "RSO 2 N( RA )-" group, where R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane radical, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-sulfonylamino group can be substituted or unsubstituted.

「O-羧基(O-carboxy)」基團係指「RC(=O)O-」基團，其中R可係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)，如本文所定義。O-羧基可係經取代或未經取代的。The "O-carboxy" group refers to the "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic radical, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

用語「酯(ester)」及「C-羧基(C-carboxy)係指「-C(=O)OR」基團，其中R可與關於O-羧基所定義者相同。酯及C-羧基可係經取代或未經取代的。The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy. Esters and C-carboxy groups can be substituted or unsubstituted.

「硝基(nitro)」係指「–NO 2」基團。 "Nitro" refers to a "-NO 2 " group.

「次磺醯基(sulfenyl)」基團係指「-SR」基團，其中R可係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。次磺醯基可係經取代或未經取代的。A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, Heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A sulfenyl group can be substituted or unsubstituted.

「亞磺醯基(sulfinyl)」係指「-S(=O)-R」基團，其中R可與關於次磺醯基所定義者相同。亞磺醯基可係經取代或未經取代的。"Sulfinyl" refers to a "-S(=O)-R" group, where R may be the same as defined for sulfenyl. A sulfinyl group can be substituted or unsubstituted.

「磺醯基(sulfonyl)」係指「SO 2R」基團，其中R可與關於次磺醯基所定義者相同。磺醯基可係經取代或未經取代的。 "Sulfonyl" refers to a "SO 2 R" group, wherein R may be the same as defined for sulfenyl. A sulfonyl group can be substituted or unsubstituted.

如本文中所使用，「鹵烷基(haloalkyl)」係指其中一或多個氫原子係經鹵素置換的烷基（例如，單鹵烷基、二鹵烷基、三鹵烷基、及多鹵烷基）。此類基團包括但不限於氯甲基、氟甲基、二氟甲基、三氟甲基、1-氯-2-氟甲基、2-氟異丁基、及五氟乙基。鹵烷基可係經取代或未經取代的。As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups can be substituted or unsubstituted.

如本文中所使用，「鹵烷氧基(haloalkoxy)」係指其中一或多個氫原子係經鹵素置換的烷氧基（例如，單鹵烷氧基、二鹵烷氧基、及三鹵烷氧基）。此類基團包括但不限於氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、1-氯-2-氟甲氧基、及2-氟異丁氧基。鹵烷氧基可係經取代或未經取代的。As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) alkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

本文中所使用之用語「胺基(amino)」及「未經取代胺基(unsubstituted amino)」係指–NH 2基團。 The terms "amino" and "unsubstituted amino" as used herein refer to a -NH 2 group.

「經單取代胺(mono-substituted amine)」基團係指「-NHR A」基團，其中R A可係烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)，如本文中所定義。R A可係經取代的或未經取代的。經單取代胺基團可例如包括單烷基胺基團、單-C 1-C 6烷基胺基團、單芳基胺基團、單-C 6-C 10芳基胺基團、及類似者。經單取代胺基團之實例包括但不限於−NH(甲基)、−NH(苯基)、及類似者。 A "mono-substituted amine" group refers to a " -NHRA " group, where RA can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, hetero Aryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. RA can be substituted or unsubstituted. Monosubstituted amine groups may, for example, include monoalkylamine groups, mono- C1 - C6 alkylamine groups, monoarylamine groups, mono- C6 - C10 arylamine groups, and similar. Examples of monosubstituted amine groups include, but are not limited to, −NH(methyl), −NH(phenyl), and the like.

「經二取代胺(di-substituted amine)」基團係指「-NR AR B」基團，其中R A及R B可獨立地係烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)，如本文中所定義。R A及R B可獨立地係經取代的或未經取代的。經二取代胺基團可例如包括二烷基胺基團、二-C 1-C 6烷基胺基團、二芳基胺基團、二-C 6-C 10芳基胺基團、及類似者。經二取代胺基團之實例包括但不限於−N(甲基) 2、−N(苯基)(甲基)、−N(乙基)(甲基)、及類似者。 A "di-substituted amine" group refers to a "-NR A R B " group, wherein R A and R B can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, Alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as described herein definition. RA and RB can independently be substituted or unsubstituted. Disubstituted amine groups may, for example, include dialkylamine groups, di-C 1 -C 6 alkylamine groups, diarylamine groups, di-C 6 -C 10 arylamine groups, and similar. Examples of disubstituted amine groups include, but are not limited to, −N(methyl) 2 , −N(phenyl)(methyl), −N(ethyl)(methyl), and the like.

如本文中所使用，「經單取代胺(烷基)(mono-substituted amine(alkyl))」係指經由低級伸烷基連接作為取代基之經單取代胺（如本文中所提供）。經單取代胺(烷基)可係經取代的或未經取代的。經單取代胺(烷基)可例如包括單烷基胺(烷基)基團、單C 1-C 6烷基胺(C 1-C 6烷基)基團、單芳基胺(烷基)基團、單C 6-C 10芳基胺(C 1-C 6烷基)基團、及類似者。經單取代胺(胺基)基團之實例包括但不限於−CH 2NH(甲基)、−CH 2NH(苯基)、−CH 2CH 2NH(甲基)、−CH 2CH 2NH(苯基)、及類似者。 As used herein, "mono-substituted amine (alkyl)" refers to a mono-substituted amine (as provided herein) attached as a substituent through a lower alkylene group. A monosubstituted amine (alkyl) can be substituted or unsubstituted. Mono-substituted amine (alkyl) groups may, for example, include monoalkylamine (alkyl) groups, mono-C 1 -C 6 alkylamine (C 1 -C 6 alkyl) groups, monoarylamine (alkyl) groups, ) group, mono C 6 -C 10 arylamine (C 1 -C 6 alkyl) group, and the like. Examples of monosubstituted amine (amino) groups include , but are not limited to, -CH2NH (methyl), -CH2NH ( phenyl), -CH2CH2NH (methyl), -CH2CH2 NH(phenyl), and the like.

如本文中所使用，「經二取代胺(烷基)(di-substituted amine(alkyl))」係指經由低級伸烷基連接作為取代基之經二取代胺（如本文中所提供）。經二取代胺(烷基)可係經取代的或未經取代的。經二取代胺(烷基)基團可例如包括二烷基胺(烷基)基團、二C 1-C 6烷基胺(C 1-C 6烷基)基團、二芳基胺(烷基)基團、二C 6-C 10芳基胺(C 1-C 6烷基)基團、及類似者。經二取代胺(烷基)之實例包括但不限於−CH 2N(甲基) 2、−CH 2N(苯基)(甲基)、−NCH 2(乙基)(甲基)、−CH 2CH 2N(甲基) 2、−CH 2CH 2N(苯基)(甲基)、−NCH 2CH 2(乙基)(甲基)、及類似者。 As used herein, "di-substituted amine (alkyl)" refers to a di-substituted amine (as provided herein) attached as a substituent through a lower alkylene group. A disubstituted amine(alkyl) can be substituted or unsubstituted. Disubstituted amine (alkyl) groups may, for example, include dialkylamine (alkyl) groups, di-C 1 -C 6 alkylamine (C 1 -C 6 alkyl) groups, diarylamine ( alkyl) group, diC 6 -C 10 arylamine (C 1 -C 6 alkyl) group, and the like. Examples of disubstituted amines (alkyl) include, but are not limited to, −CH 2 N(methyl) 2 , −CH 2 N(phenyl)(methyl), −NCH 2 (ethyl)(methyl), −CH 2 N(phenyl)(methyl), −CH 2 N(methyl) CH2CH2N (methyl ) 2 , -CH2CH2N ( phenyl )(methyl), -NCH2CH2 ( ethyl)(methyl), and the like.

當未指定取代基的數目（例如，鹵烷基）時，則可能有一或多個取代基存在。例如，「鹵烷基(haloalkyl)」可包括一或多個相同或不同的鹵素。作為另一個實例，「C 1-C 3烷氧基苯基(C 1-C 3alkoxyphenyl)」可包括一或多個相同或不同之含有一、二、或三個原子的烷氧基。 When the number of substituents is not specified (eg, haloalkyl), then one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C 1 -C 3 alkoxyphenyl (C 1 -C 3 alkoxyphenyl)" may include one or more same or different alkoxy groups containing one, two, or three atoms.

如本文中所使用，基表示具有單個未成對電子之物種，使得含有該基之物種可共價鍵結至另一種物種。因此，在此上下文中，基不一定是自由基。相反地，基表示較大分子之特定部分。用語「基(radical)」可與用語「基團(group)」互換使用。As used herein, a group means a species with a single unpaired electron such that the species containing the group can covalently bond to another species. Therefore, radicals are not necessarily free radicals in this context. In contrast, a group denotes a specific portion of a larger molecule. The term "radical" is used interchangeably with the term "group".

用語「醫藥上可接受之鹽(pharmaceutically acceptable salt)」係指不會對其所投予至之生物體造成顯著刺激且不會使化合物之生物活性及性質無效化的化合物之鹽。在一些實施例中，鹽係化合物之酸加成鹽。醫藥鹽可藉由使化合物與無機酸反應而獲得，無機酸諸如氫鹵酸（例如，氫氯酸或氫溴酸）、硫酸、硝酸、及磷酸（諸如2,3-二羥丙基磷酸二氫鹽）。醫藥鹽亦可藉由使化合物與有機酸反應而獲得，有機酸諸如脂族或芳族羧酸或磺酸，例如甲酸、乙酸、琥珀酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、菸鹼酸、甲磺酸、乙磺酸、對甲苯磺酸、三氟乙酸、苯甲酸、水楊酸、2-側氧戊二酸或萘磺酸。醫藥鹽亦可藉由使化合物與鹼反應以形成鹽而獲得，鹽諸如銨鹽、鹼金屬鹽（諸如鈉鹽、鉀鹽、或鋰鹽）、鹼土金屬鹽（諸如鈣鹽或鎂鹽）、碳酸鹽、碳酸氫鹽、有機鹼（諸如二環己基胺、N-甲基-D-還原葡糖胺、參(羥甲基)甲基胺、C 1-C 7烷基胺、環己基胺、三乙醇胺、乙二胺）之鹽、及與胺基酸（諸如精胺酸及離胺酸）之鹽。針對式(I)之化合物，所屬技術領域中具有通常知識者理解，當鹽係藉由基於氮之基團（例如，NH 2）的質子化而形成時，基於氮之基團可與正電荷締合（例如，NH 2可變成NH 3 +），且該正電荷可由帶負電荷之相對離子（諸如Cl -）平衡。 The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acids), sulfuric acid, nitric acid, and phosphoric acids (such as 2,3-dihydroxypropyl phosphate di hydrogen salt). Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic acid, Alkaline acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salt, alkali metal salt (such as sodium, potassium, or lithium salt), alkaline earth metal salt (such as calcium or magnesium salt), Carbonates, bicarbonates, organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, ginseng(hydroxymethyl)methylamine, C 1 -C 7 alkylamines, cyclohexylamine , triethanolamine, ethylenediamine), and salts with amino acids (such as arginine and lysine). With respect to compounds of formula (I), those of ordinary skill in the art understand that when salts are formed by protonation of nitrogen-based groups (e.g., NH 2 ), the nitrogen-based groups can be associated with a positive charge association (for example, NH 2 can become NH 3 + ), and this positive charge can be balanced by a negatively charged counterion such as Cl − .

用語「CDK7抑制(CDK7 inhibition)」及類似用語係指抑制CDK7蛋白之活性或功能。類似地，用語「CDK7抑制劑(CDK7 inhibitor)」係指抑制CDK7蛋白之功能的藥劑（包括小分子及蛋白質）。如所屬技術領域中具有通常知識者所將理解，有許多種評估蛋白質結合交互作用之方法，包括但不限於共免疫沉澱、螢光共振能量傳遞(FRET)、表面電漿共振(SPR)、及螢光偏振/各向異性。The term "CDK7 inhibition" and similar terms refer to the inhibition of the activity or function of the CDK7 protein. Similarly, the term "CDK7 inhibitor" refers to agents (including small molecules and proteins) that inhibit the function of CDK7 protein. As will be appreciated by those of ordinary skill in the art, there are many methods of assessing protein binding interactions, including but not limited to co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR), and Fluorescence polarization/anisotropy.

應理解，在本文所述之具有一或多個掌性中心之任何化合物中，若未明確指示絕對立體化學，則各中心可獨立地具有R-組態、或S-組態、或其混合物。因此，本文中所提供之化合物可係鏡像異構地純的、鏡像異構地富集的外消旋混合物、非鏡像異構地純的、非鏡像異構地富集的或立體異構的混合物。此外，應當理解，在具有一或多個雙鍵產生幾何異構物（可定義為E或Z）之任何本文中所述化合物中，各雙鍵可獨立地係E或Z或其混合。同樣地，應理解，在任何所述化合物中，亦意欲將所有互變異構形式包括在內。It is understood that in any compound described herein having one or more chiral centers, unless absolute stereochemistry is explicitly indicated, each center may independently have the R-configuration, or the S-configuration, or mixtures thereof . Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixture. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds yielding geometric isomers (which may be defined as E or Z), each double bond may independently be E or Z or a mixture thereof. Likewise, it is to be understood that in any such compound, all tautomeric forms are also intended to be included.

應理解，在本文中揭示之化合物具有未填滿價數時，則價數應以氫或其同位素填滿，例如氫-1（氕）及氫-2（氘）。It is understood that where compounds disclosed herein have unfilled valencies, then the valences should be filled with hydrogen or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

應理解，本文所述之化合物可經同位素標示。以諸如氘之同位素取代可得到由較高代謝穩定性帶來的某些治療優點，例如體內半衰期增長或劑量需求降低。在化合物結構中表示之各化學元素可包括該元素之任何同位素。例如，在化合物結構中，氫原子可明確揭示或理解成存在於化合物中。在化合物之可能存在氫原子的任何位置處，氫原子可係氫之任何同位素，包括但不限於氫-1（氕）及氫-2（氘）。因此，在本文中參照之化合物涵蓋所有潛在同位素形式，除非上下文清楚另行表明。It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Wherever a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references herein to compounds encompass all potential isotopic forms, unless the context clearly dictates otherwise.

應理解，本文所述之方法及組合包括結晶形式（亦稱為多形體，其包括化合物之相同元素組成之不同晶體堆積排列）、非晶相、鹽、溶劑合物、及水合物。在一些實施例中，本文所述之化合物以與醫藥上可接受之溶劑（諸如水、乙醇、或類似者）之溶劑合形式存在。在其他實施例中，本文所述之化合物以非溶劑合形式存在。溶劑合物含有化學計量或非化學計量之量的溶劑，且可與醫藥上可接受之溶劑（諸如水、乙醇、或類似者）在結晶程序期間形成。當溶劑係水時即形成水合物，當溶劑係醇時即形成醇合物。此外，本文中所提供之化合物可以非溶劑合形式以及溶劑合形式存在。一般而言，針對本文中所提供之化合物及方法的目的，將溶劑合形式視為等同於非溶劑合形式。It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal-packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated form with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed with pharmaceutically acceptable solvents such as water, ethanol, or the like during the crystallization procedure. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

當提供數值之範圍時，應理解範圍之上限及下限以及在上限及下限之間的各介入數值皆涵蓋於實施例之中。Where a range of values is provided, it is understood that the upper and lower limits of the range, as well as each intervening value therebetween, are encompassed in the examples.

除非另外明確說明，否則本申請案中所使用之用語、及片語、及其變化（尤其在隨附申請專利範圍中）應理解為開放式的而非限制性的。作為前述者之實例，用語「包括(including)」應解讀為意指「包括但不限於(including, without limitation及including but not limited to)」或類似者；如本文中所使用之用語「包含(comprising)」與「包括(including)、含有(containing)、或「其特徵為(characterized by)」係同義詞，且係包含式或開放式且不排除額外、未列舉之元件或方法步驟；用語「具有(having)」應解讀為「具有至少(having at least)」；用語「包括(include)」應解讀為「包括但不限於」；用語「實例(example)」係用於提供討論項目之例示性例子而非其詳盡或限制性列表；且用語如「較佳地(preferably)」、「較佳的(preferred)」、「所欲(desired或desirable)」及類似意義文字的使用，不應理解為暗示某些特徵對於結構或功能而言係關鍵、必要、甚或重要的，反而只是意圖強調可在一具體實施例中利用或不利用之替代或額外特徵。此外，用語「包含(comprising)」應與片語「至少具有(having at least)」或「至少包括(including at least)」同義地解釋。當用於化合物、組成物、或裝置之上下文中時，用語「包含」意指化合物、組成物、或裝置至少包括所列舉特徵或組分，但亦可包括額外特徵或組分。Unless expressly stated otherwise, the terms and phrases used in this application, and variations thereof (particularly in the appended claims), should be interpreted as open-ended and not limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation and including but not limited to" or the like; as used herein, the term "including ( "comprising)" is synonymous with "including (including), containing (containing), or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term " The term "having" should be read as "having at least"; the term "include" should be read as "including but not limited to"; the term "example" is used to provide an illustration of the item under discussion are not intended to be an exhaustive or limiting list; and the use of terms such as "preferably", "preferred", "desired or desirable" and words of similar meaning should not It is understood to imply that certain features are critical, necessary, or even important to structure or function, but instead is only intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Furthermore, the term "comprising" should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

關於在本文中使用實質上任何複數及/或單數用語，所屬技術領域中具有通常知識者可視適合上下文及/或應用之情況，從複數轉換成單數及/或從單數轉換成複數。各種單數/複數排列組合可在本文中明確闡述以求清晰。不定冠詞「一（a或an）」並不排除複數。在互不相同的附屬項中列舉某些措施的單純事實，並不表示這些措施之組合無法有益地使用。申請專利範圍中之任何元件符號不應解讀為範圍限制。 化合物 With respect to the use of substantially any plural and/or singular terms herein, one of ordinary skill in the art may switch from the plural to the singular and/or from the singular to the plural as appropriate to the context and/or application. Various singular/plural permutations may be explicitly set forth herein for clarity. The indefinite article "one (a or an)" does not exclude the plural. The mere fact that certain measures are listed in mutually different subparagraphs does not indicate that a combination of these measures cannot be used to advantage. Any element symbols in claims should not be construed as limiting the scope. compound

本文所揭示之一些實施例係關於一種式(I)之化合物、或其醫藥上可接受之鹽： (I) Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof: (I)

在式(I)中之R 1及R 2可各自獨立地係氫、鹵素、CN、烷基、烷氧基、鹵烷基、羥烷基、環烷基、NHR 5a、或NR 5aR 5b。在一實施例中，R 1及R 2中之至少一者係氫。在另一實施例中，R 1及R 2中之至少一者係鹵素。在另一實施例中，R 1及R 2中之至少一者係CN。在另一實施例中，R 1及R 2中之至少一者係烷基，例如C 1-3烷基。在另一實施例中，R 1及R 2中之至少一者係烷氧基，例如C 1-3烷氧基。在另一實施例中，R 1及R 2中之至少一者係鹵烷基，例如C 1-3鹵烷基。在另一實施例中，R 1及R 2中之至少一者係羥烷基，例如C 1-3羥烷基。在另一實施例中，R 1及R 2中之至少一者係環烷基，例如C 3-6環烷基。在另一實施例中，R 1及R 2中之至少一者係NHR 5a。在另一實施例中，R 1及R 2中之至少一者係NR 5aR 5b。在另一實施例中，R 1及R 2中之至少一者係氫、氯基、氟基、甲基、羥乙基、或三氟甲基。 In formula (I), R 1 and R 2 can be independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , or NR 5a R 5b . In one embodiment, at least one of R 1 and R 2 is hydrogen. In another embodiment, at least one of R1 and R2 is halogen. In another embodiment, at least one of R 1 and R 2 is CN. In another embodiment, at least one of R 1 and R 2 is alkyl, such as C 1-3 alkyl. In another embodiment, at least one of R 1 and R 2 is alkoxy, such as C 1-3 alkoxy. In another embodiment, at least one of R 1 and R 2 is haloalkyl, such as C 1-3 haloalkyl. In another embodiment, at least one of R and R is hydroxyalkyl, such as C 1-3 hydroxyalkyl. In another embodiment, at least one of R and R is cycloalkyl, such as C 3-6 cycloalkyl. In another embodiment, at least one of R 1 and R 2 is NHR 5a . In another embodiment, at least one of R 1 and R 2 is NR 5a R 5b . In another embodiment, at least one of R and R is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl.

在式(I)中之R 3可係經取代或未經取代的C 3-C 8環烷基、或C 3-C 8雜環基。在各種實施例中，經取代之C 3-C 8環烷基、或C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基、烷氧基、鹵烷基、環烷基、雜環基、NHR 5a、NR 5aR 5b、或OR 6之基團所取代。在一實施例中，R 3係經取代之C 3-C 8環烷基。在一實施例中，R 3係未經取代之C 3-C 8環烷基。在一實施例中，R 3係經取代之C 3-C 8雜環基。在一實施例中，R 3係未經取代之C 3-C 8雜環基。在一實施例中，R 3係哌啶基、甲基哌啶基、二甲基哌啶基、二氟哌啶基、吡咯啶基、(N-乙基胺基)環丁基、(N-乙基胺基)環戊基、氮雜螺辛基、氮雜螺壬基、或氧雜氮雜螺癸基。 R 3 in formula (I) may be substituted or unsubstituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl. In various embodiments, the substituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl is one or more independently selected from halogen, alkyl, alkoxy, haloalkyl, Cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 are substituted. In one embodiment, R 3 is substituted C 3 -C 8 cycloalkyl. In one embodiment, R 3 is unsubstituted C 3 -C 8 cycloalkyl. In one embodiment, R 3 is a substituted C 3 -C 8 heterocyclyl. In one embodiment, R 3 is an unsubstituted C 3 -C 8 heterocyclyl. In one embodiment, R is piperidinyl , methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N -ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxazaspirodecyl.

在式(I)中之R 4可係鹵素、CN、烷基、環烷基、-NR 7R 8、OR 6、-CO 2R 6、或-C(O)-NR 7R 8。在一實施例中，R 4係鹵素。在一實施例中，R 4係CN。在一實施例中，R 4係烷基，例如C 1-3烷基。在一實施例中，R 4係環烷基，例如C 1-3環烷基。在一實施例中，R 4係-NR 7R 8。在一實施例中，R 4係OR 6。在一實施例中，R 4係-CO 2R 6。在一實施例中，R 4係-C(O)-NR 7R 8。在各種實施例中，R 4之R 7及R 8各獨立地係未經取代之烷基，例如C 1-3烷基。在其他實施例中，R 4之R 7及R 8與其所連接之N一起形成未經取代或經取代的C 3-C 8雜環基。在各種實施例中，R 4係CN、N,N-二甲基醯胺基、N,N-二乙基醯胺基、 、 、 、 、或 。 R 4 in formula (I) may be halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , -CO 2 R 6 , or -C(O)-NR 7 R 8 . In one embodiment, R 4 is halogen. In one embodiment, R 4 is CN. In one embodiment, R 4 is alkyl, such as C 1-3 alkyl. In one embodiment, R 4 is cycloalkyl, such as C 1-3 cycloalkyl. In one embodiment, R 4 is -NR 7 R 8 . In one embodiment, R 4 is OR 6 . In one embodiment, R 4 is -CO 2 R 6 . In one embodiment, R 4 is -C(O)-NR 7 R 8 . In various embodiments, R 7 and R 8 of R 4 are each independently unsubstituted alkyl, such as C 1-3 alkyl. In other embodiments, R 7 and R 8 of R 4 together with the N to which they are attached form an unsubstituted or substituted C 3 -C 8 heterocyclic group. In various embodiments, R is CN, N,N-dimethylamido, N,N-diethylamido, , , , ,or .

在式(I)中之各R 5a、R 5b、及R 6可獨立地係氫、烷基、鹵烷基、或環烷基。在一實施例中，R 5a、R 5b、及R 6中之至少一者係氫。在一實施例中，R 5a、R 5b、及R 6中之至少一者係烷基，例如C 1-3烷基。在一實施例中，R 5a、R 5b、及R 6中之至少一者係鹵烷基，例如C 1-3鹵烷基。在一實施例中，R 5a、R 5b、及R 6中之至少一者係環烷基，例如C 3-6環烷基。 Each of R 5a , R 5b , and R 6 in formula (I) may be independently hydrogen, alkyl, haloalkyl, or cycloalkyl. In one embodiment, at least one of R 5a , R 5b , and R 6 is hydrogen. In one embodiment, at least one of R 5a , R 5b , and R 6 is an alkyl group, such as a C 1-3 alkyl group. In one embodiment, at least one of R 5a , R 5b , and R 6 is haloalkyl, such as C 1-3 haloalkyl. In one embodiment, at least one of R 5a , R 5b , and R 6 is cycloalkyl, such as C 3-6 cycloalkyl.

在式(I)中之R 7及R 8可各自獨立地係氫、經取代或未經取代之烷基、或經取代或未經取代之環烷基。在各種實施例中，經取代之烷基或經取代之環烷基係經1至3個獨立地選自鹵素、OR 6、CN、烷基、NHR 5a、或NR 5aR 5b所取代。在替代實施例中，在式(I)中之R 7及R 8與其所連接之N一起形成未經取代或經取代的C 3-C 8雜環基。在一實施例中，該經取代之C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基（例如C 1-3烷基）、烷氧基（例如C 1-3烷氧基）、鹵烷基（例如C 1-3鹵烷基）、環烷基（例如C 3-6環烷基）、雜環基、NHR 5a、NR 5aR 5b、或OR 6之基團所取代。在一實施例中，R 7及R 8中之至少一者獨立地係氫、經取代或未經取代之烷基（例如C 1-3烷基）、或經取代或未經取代之環烷基（例如C 3-6環烷基）。在一實施例中，R 7及R 8中之至少一者係氫。在一實施例中，R 7及R 8中之至少一者係經取代之烷基。在一實施例中，R 7及R 8中之至少一者係未經取代之烷基（例如C 1-3烷基）。在一實施例中，R 7及R 8中之至少一者係經取代之環烷基（例如經取代之C 3-6環烷基）。在一實施例中，R 7及R 8中之至少一者係未經取代之環烷基（例如C 3-6環烷基）。在一實施例中，在式(I)中之R 7及R 8與其所連接之N一起形成未經取代的C 3-C 8雜環基。在一實施例中，在式(I)中之R 7及R 8與其所連接之N一起形成經取代的C 3-C 8雜環基。 R 7 and R 8 in formula (I) may each independently be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In various embodiments, the substituted alkyl or substituted cycloalkyl is substituted with 1 to 3 independently selected from halogen, OR 6 , CN, alkyl, NHR 5a , or NR 5a R 5b . In alternative embodiments, R 7 and R 8 in formula (I) together with the N to which they are attached form an unsubstituted or substituted C 3 -C 8 heterocyclyl. In one embodiment, the substituted C 3 -C 8 heterocyclyl is selected from one or more independently selected from halogen, alkyl (such as C 1-3 alkyl), alkoxy (such as C 1-3 3 alkoxy), haloalkyl (such as C 1-3 haloalkyl), cycloalkyl (such as C 3-6 cycloalkyl), heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 group replaced. In one embodiment, at least one of R and R is independently hydrogen, substituted or unsubstituted alkyl (eg, C 1-3 alkyl), or substituted or unsubstituted cycloalkane group (such as C 3-6 cycloalkyl). In one embodiment, at least one of R7 and R8 is hydrogen. In one embodiment, at least one of R and R is substituted alkyl. In one embodiment, at least one of R 7 and R 8 is unsubstituted alkyl (eg, C 1-3 alkyl). In one embodiment, at least one of R and R is substituted cycloalkyl (eg, substituted C 3-6 cycloalkyl). In one embodiment, at least one of R and R is unsubstituted cycloalkyl (eg , C 3-6 cycloalkyl). In one embodiment, R 7 and R 8 in formula (I) together with the N to which they are attached form an unsubstituted C 3 -C 8 heterocyclic group. In one embodiment, R 7 and R 8 in formula (I) together with the N to which they are attached form a substituted C 3 -C 8 heterocyclyl.

在式(I)中之X可係N或CR 9；Q 1可係C或N；Q 2可係CH或N；且Q 3可係CH、N、或NH。在一實施例中，當Q 1係N，則Q 3係N。在一實施例中，X係N。在另一實施例中，X係CR 9。在一實施例中，Q 1係C。在另一實施例中，Q 1係N且Q 3係N。在一實施例中，Q 2係CH。在另一實施例中，Q 2係N。在一實施例中，Q 3係CH。在另一實施例中，Q 3係N。在另一實施例中，Q 3係NH。 X in formula (I) can be N or CR 9 ; Q 1 can be C or N; Q 2 can be CH or N; and Q 3 can be CH, N, or NH. In one embodiment, when Q 1 is N, then Q 3 is N. In one embodiment, X is N. In another embodiment, X is CR9 . In one embodiment, Q1 is C. In another embodiment, Q1 is N and Q3 is N. In one embodiment, Q2 is CH. In another embodiment, Q2 is N. In one embodiment, Q3 is CH. In another embodiment, Q3 is N. In another embodiment, Q3 is NH.

在式(I)中之R 9可係氫、 、 、或 。在一實施例中，R 9係氫。在一實施例中，R 9係 。在一實施例中，R 9係 。在一實施例中，R 9係 。在一實施例中，R 9係 、 、 、 、或 。在式(I)中之各n可獨立地係0、1、2、3、或4。在一實施例中，R 9中之n係1。在另一實施例中，R 9中之n係2。 R in formula (I) can be hydrogen, , ,or . In one embodiment, R9 is hydrogen. In one embodiment, R9 is . In one embodiment, R9 is . In one embodiment, R9 is . In one embodiment, R9 is , , , ,or . Each n in formula (I) can be 0, 1, 2, 3, or 4 independently. In one embodiment, n in R9 is 1. In another embodiment, n in R9 is 2.

在式(I)中之各R 10可獨立地係氫、烷基（例如C 1-3烷基)、鹵烷基（例如C 1-3鹵烷基）、或環烷基（例如C 3-6環烷基）。在一實施例中，各R 10係C 1-3烷基。在式(I)之各種實施例中，當各R 10獨立地係甲基或乙基，式(I)不係 。 Each R 10 in formula (I) can be independently hydrogen, alkyl (such as C 1-3 alkyl), haloalkyl (such as C 1-3 haloalkyl), or cycloalkyl (such as C 3 -6 cycloalkyl). In one embodiment, each R 10 is C 1-3 alkyl. In various embodiments of formula (I), when each R 10 is independently methyl or ethyl, formula (I) is not .

在式(I)中之Y及Z可各自獨立地係N或CH。在一實施例中，Y及Z中之至少一者係N。在一實施例中，Y及Z中之至少一者係CH。Y and Z in formula (I) may each independently be N or CH. In one embodiment, at least one of Y and Z is N. In one embodiment, at least one of Y and Z is CH.

在各種實施例中，式(I)之化合物具有如表2至6、及/或以下之實例中之任一者所描述之化學結構。 合成 In various embodiments, the compound of Formula (I) has a chemical structure as described in any one of Tables 2-6, and/or the Examples below. synthesis

式(I)化合物、或其醫藥上可接受之鹽可由所屬技術領域中具有通常知識者使用已知技術並由本文提供之詳細教示指引以各種方式製造，包括下文提供的實例。例如，在一實施例中，根據圖1中所繪示之通用方案製備式(I)化合物。式A及B之化合物可經歷AlCl 3誘導之雜芳基化反應、或金屬催化偶合反應，接著在X上安裝R 9或R 4之完全修飾。在圖1中，L代表適當的脫離基，其經由芳族親核取代或Buchwald胺化被R 3胺置換。經由氫解反應或酸水解移除保護基提供式(I)化合物、或其醫藥上可接受之鹽。形成起始化合物或其他前驅物所需之任何初步反應步驟可由所屬技術領域中具有通常知識者進行。在圖1及繪示之式中，變項R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7、R 8、R 9、R 10、X、Y、Z、Q 1、Q 2、Q 3、及n可如本文別處所述，並且將所涉及的合成轉化（如所屬技術領域中具有通常知識者所理解）納入考量。 醫藥組成物 Compounds of formula (I), or pharmaceutically acceptable salts thereof, can be manufactured in various ways by those of ordinary skill in the art using known techniques and guided by the detailed teachings provided herein, including the examples provided below. For example, in one example, compounds of formula (I) are prepared according to the general scheme depicted in FIG. 1 . Compounds of formulas A and B can undergo AlCl 3 -induced heteroarylation reactions, or metal catalyzed coupling reactions, followed by full modification of R 9 or R 4 installed on X. In Figure 1, L represents an appropriate leaving group, which is displaced by R3 amine via aromatic nucleophilic substitution or Buchwald amination. Removal of the protecting group via hydrogenolysis or acid hydrolysis provides a compound of formula (I), or a pharmaceutically acceptable salt thereof. Any preliminary reaction steps required to form starting compounds or other precursors can be performed by one of ordinary skill in the art. In Figure 1 and the formula shown, the variables R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , R 9 , R 10 , X, Y, Z , Q 1 , Q 2 , Q 3 , and n may be as described elsewhere herein, taking into account the synthetic transformations involved (as understood by those of ordinary skill in the art). Pharmaceutical composition

本文中所述之一些實施例係關於一種醫藥組成物，其可包括有效量之一或多種本文中所述之化合物（例如式(I)之化合物、或其醫藥上可接受之鹽）及醫藥上可接受之載劑、稀釋劑、賦形劑、或其組合。Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutical The above acceptable carrier, diluent, excipient, or a combination thereof.

用語「醫藥組成物(pharmaceutical composition)」係指本文中所揭示之一或多種化合物及/或鹽與其他化學組分（諸如稀釋劑或載劑）之混合物。醫藥組成物促進化合物向生物體之投予。醫藥組成物亦可藉由使化合物與無機酸或有機酸（諸如氫氯酸、氫溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、對甲苯磺酸、及水楊酸）反應來獲得。醫藥組成物通常將針對特定意圖投予途徑設計。The term "pharmaceutical composition" refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components such as diluents or carriers. Pharmaceutical compositions facilitate the administration of compounds to organisms. Pharmaceutical compositions can also be prepared by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. to get. Pharmaceutical compositions will generally be designed for a particular intended route of administration.

用語「生理上可接受之(physiologically acceptable)」定義載劑、稀釋劑、或賦形劑，其不會消除化合物之生物活性及性質，亦不會對預期遞送組成物之動物引起明顯損傷或損害。The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not abolish the biological activity and properties of the compound, nor does it cause significant injury or damage to the animal to which the composition is intended to be delivered .

如本文中所使用，「載劑(carrier)」係指促進化合物併入細胞或組織中之化合物。例如（但不限於），二甲基亞碸(DMSO)係經常利用的載劑，其促進許多有機化合物被攝入對象的細胞或組織中。As used herein, "carrier" refers to a compound that facilitates the incorporation of the compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a frequently utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

如本文中所使用，「稀釋劑(diluent)」係指醫藥組成物中缺乏明顯藥理學活性但可能為醫藥上必需或所欲之成分。例如，稀釋劑可用於增加質量過小而無法用於製造及/或投予之有效藥物的體積。其亦可係用於溶解將藉由注射、攝取或吸入投予之藥物的液體。所屬技術領域中常見形式的稀釋劑為緩衝水溶液，諸如但不限於模擬人類血液之pH及等滲性之磷酸鹽緩衝鹽水。As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks significant pharmacological activity but may be medically necessary or desirable. For example, diluents can be used to increase the volume of an effective drug whose mass is too small to manufacture and/or administer. It may also be a liquid used to dissolve a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, but not limited to, phosphate buffered saline that mimics the pH and isotonicity of human blood.

如本文中所使用，「賦形劑(excipient)」係指基本上惰性的物質，其經添加至醫藥組成物中以向該組成物提供（但不限於）體積、稠度、穩定性、結合能力、潤滑、崩解能力等。例如，諸如抗氧化劑及金屬螯合劑之穩定劑係賦形劑。在一實施例中，醫藥組成物包含抗氧化劑及/或金屬螯合劑。「稀釋劑(diluent)」係一種類型的賦形劑。As used herein, "excipient" means a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity to the composition , lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition includes antioxidants and/or metal chelating agents. A "diluent" is a type of excipient.

在本文中描述之醫藥組成物本身可向人類患者投予，或可以其中彼等與其他活性成分（如在組合療法中）、或載劑、稀釋劑、賦形劑或其組合混合之醫藥組成物向人類患者投予。適當配方取決於選擇的投予途徑。用於本文所述之化合物的配方及投予之技術係所屬技術領域中具有通常知識者已知的。The pharmaceutical compositions described herein may be administered to human patients by themselves, or may be pharmaceutical compositions in which they are admixed with other active ingredients (as in combination therapy), or carriers, diluents, excipients, or combinations thereof administered to human patients. Proper formulation depends upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those of ordinary skill in the art.

在本文中揭示之醫藥組成物可以本身已知之方式製造，例如藉由習知之混合、溶解、造粒、糖衣錠製造、研調、乳化、囊封、包封、或製錠程序。此外，所含有的活性成分之量可有效達成其意圖目的。在本文中揭示之醫藥組合中使用的許多化合物可提供為含有醫藥上相容的相對離子之鹽。The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or tableting procedures. Furthermore, the active ingredient is contained in an amount effective for its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts with pharmaceutically compatible counterions.

所屬技術領域存在多種投予化合物、鹽、及/或組成物之技術，包括但不限於口服、直腸、肺、外用、氣溶膠、注射、輸注、及非經腸遞送，包括肌肉內、皮下、靜脉內、髓內注射、鞘內、直接心室內、腹膜內、鼻內、及眼內注射。在一些實施例中，式(I)之化合物、或其醫藥上可接受之鹽可經口服投予。Various techniques for administering compounds, salts, and/or compositions exist in the art, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, Intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.

亦可以局部而非全身方式投予化合物、鹽、及/或組成物，例如經由將通常呈貯劑或持續釋放配方之化合物直接注射或植入至感染區域中。另外，可以標靶藥物遞送系統（例如塗佈組織特異性抗體之脂質體）投予化合物。脂質體將靶向器官且由器官選擇性吸收。例如，可能需要鼻內或肺遞送以靶向呼吸疾病或病況。Compounds, salts, and/or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound, usually in a depot or sustained release formulation, into the affected area. Additionally, the compounds can be administered in a targeted drug delivery system such as liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. For example, intranasal or pulmonary delivery may be desired to target respiratory diseases or conditions.

所欲時，組成物可呈現於可含有一或多個（含有活性成分之）單位劑型之包裝或分配裝置中。包裝可例如包含金屬或塑膠箔，例如泡殼包裝。包裝或分配器裝置可隨附投予說明。包裝或分配器亦可隨附與該容器相關聯之通知來規範藥品的製造、使用、或銷售，通知之形式係由政府機構規定，該通知反映該機構核准該藥物形式用於人類或獸醫投予。舉例來說，該通知可係美國食品與藥品管理局批准用於處方藥的標籤或產品仿單。亦可製備可包括在相容醫藥載劑中配製的本文描述之化合物及/或鹽的組成物、置於適當容器中並標示用來治療所指示之病況。 治療用途及方法 The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms (containing the active ingredient). The pack may eg comprise metal or plastic foil, eg a blister pack. The pack or dispenser unit may be accompanied by administration instructions. The package or dispenser may also be accompanied by a notice associated with the container regulating the manufacture, use, or sale of the drug in a form prescribed by a government agency reflecting the agency's approval of the drug form for human or veterinary administration. give. For example, the notice could be a label or a product leaflet approved by the Food and Drug Administration for a prescription drug. Compositions, which may include compounds described herein and/or salts formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container and labeled for treatment of the indicated condition. Therapeutic uses and methods

本文中所述之一些實施例關於一種用於治療本文中所述之癌症或腫瘤之方法，其可包括向患有本文中所述之癌症或腫瘤的對象投予有效量之本文中所述之化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）或包括本文中所述之化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）之醫藥組成物。本文中所述之其他實施例關於一種有效量之本文所述之化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）或包括本文中所述之化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）之醫藥組成物用於製造用於治療本文中所述之癌症或腫瘤之藥劑之用途。本文中所述之其他實施例關於一種有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）或包括本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）之醫藥組成物，其用於治療本文中所述之癌症或腫瘤。Some embodiments described herein pertain to a method for treating a cancer or tumor described herein, which may comprise administering to a subject suffering from a cancer or tumor described herein an effective amount of the A compound (eg, a compound of formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of formula (I) ) compound, or a pharmaceutically acceptable salt thereof), for the manufacture of a medicament for treating cancer or tumors described herein. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of formula (I) compound, or a pharmaceutically acceptable salt thereof), for the treatment of cancer or tumor as described herein.

本文中所述之一些實施例關於一種用於抑制本文中所述惡性生長或腫瘤之複製之方法，該方法可包括使該生長或該腫瘤與有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）接觸。本文中所述之其他實施例關於一種有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）用於製造用於抑制本文中所述之惡性生長或腫瘤之複製之藥劑之用途。在一些實施例中，該用途可包括使該生長或腫瘤與該藥劑接觸。本文中所述之再其他實施例關於一種有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽），其用於抑制本文中所述之惡性生長或腫瘤之複製。Some embodiments described herein pertain to a method for inhibiting the replication of a malignant growth or tumor described herein, which method may comprise combining the growth or the tumor with an effective amount of a compound described herein (e.g., formula ( I) contact with the compound, or its pharmaceutically acceptable salt). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for the manufacture of a method for inhibiting the malignant growth or Use of agents for tumor replication. In some embodiments, the use can comprise contacting the growth or tumor with the agent. Yet other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the malignant growth or Tumor replication.

本文中所述之一些實施例關於一種用於治療本文中所述之癌症之方法，該方法可包括使本文中所述之惡性生長或腫瘤與有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）接觸。本文中所述之其他實施例關於一種有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽）用於製造用於治療本文中所述之癌症之藥劑的用途。在一些實施例中，該用途包括使本文中所述之惡性生長或腫瘤與該藥劑接觸。本文中所述之又其他實施例關於一種有效量之本文中所述化合物（例如，式(I)化合物、或其醫藥上可接受之鹽），其用於接觸本文中所述之惡性生長或腫瘤，其中該惡性生長或腫瘤係導因於本文中所述之癌症。Some embodiments described herein pertain to a method for treating a cancer described herein, which method may comprise combining a malignant growth or tumor described herein with an effective amount of a compound described herein (e.g., formula ( I) contact with the compound, or its pharmaceutically acceptable salt). Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating the cancer described herein the use of. In some embodiments, the use comprises contacting a malignant growth or tumor described herein with the agent. Yet other embodiments described herein pertain to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth or A tumor, wherein the malignant growth or tumor results from a cancer as described herein.

適合的惡性生長、癌症、及腫瘤之實例包括但不限於：泌尿上皮癌、子宮癌、結腸直腸癌、乳癌、肺癌、卵巢癌、胃癌、肝膽癌、胰臟癌、子宮頸癌、***癌、血液癌、肉瘤、皮膚癌、或神經膠質瘤。Examples of suitable malignant growths, cancers, and tumors include, but are not limited to: urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, liver and gallbladder cancer, pancreatic cancer, cervical cancer, prostate cancer, Blood cancer, sarcoma, skin cancer, or glioma.

如本文中所使用，「對象(subject)」係指作為治療、觀察、或實驗之目標的動物。「動物(animal)」包括冷血及溫血脊椎動物及無脊椎動物，例如魚、甲殼類動物、爬蟲類及特別是哺乳動物。「哺乳動物(mammal)」包括但不限於小鼠、大鼠、兔、天竺鼠、犬、貓、綿羊、山羊、牛、馬、靈長類動物，諸如猴、黑猩猩、及猿，且特別是人類。在一些實施例中，對象可以是人。在一些實施例中，對象可以是兒童及/或嬰兒，例如患有發燒的兒童或嬰兒。在其他實施例中，對象可係成人。As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a person. In some embodiments, the subject may be a child and/or an infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

如本文中所使用，用語「治療(treat, treating, treatment, therapeutic)」及「療法(therapy)」不必然意指完全治癒或消除疾病或病況。可將疾病或病況之任何非所欲的徵象或症狀有任何程度的任何減輕視為治療及/或療法。另外，治療可包括可使對象對福祉或外觀的整體感覺惡化之行動。As used herein, the terms "treat, treating, treatment, therapeutic" and "therapy" do not necessarily mean complete cure or elimination of a disease or condition. Any alleviation to any degree of any undesirable sign or symptom of a disease or condition may be considered treatment and/or therapy. Additionally, treatment can include actions that can worsen a subject's overall sense of well-being or appearance.

用語「治療有效量(therapeutically effective amount)」及「有效量(effective amount)」用於指示引發指示生物或藥物反應之活性化合物或醫藥製劑的量。例如，治療有效量之化合物、鹽、或組成物可係預防、減輕、或改善疾病或病況之症狀、或延長所治療對象之存活所需的量。此反應可以在組織、系統、動物、或人類中發生，且包括減輕所治療疾病或病況之徵象或症狀。鑒於在本文中提供之揭露，有效量之判定完全在所屬技術領域中具有通常知識者之能力範圍以內。作為劑量所需之本文中所揭示之化合物的治療有效量將取決於投予途徑、所治療的動物類型（包括人類）、及所考慮的特定動物之身體特徵。可調整劑量以達到所預的效果，但是取決於諸如體重、飲食、併用藥物、及所屬醫學領域中具有通常知識者將認識到的其他因素之因素。The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of an active compound or pharmaceutical agent that elicits an indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound, salt, or composition may be that amount required to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or prolong the survival of the subject being treated. The response can occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. In view of the disclosure provided herein, determination of an effective amount is well within the ability of one of ordinary skill in the art. The therapeutically effective amount of a compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant drugs, and other factors as will be recognized by those of ordinary skill in the medical art.

例如，有效量之化合物係導致以下結果之量：(a)由癌症引起之一或多種症狀減少、減輕、或消失，(b)腫瘤大小減小，(c)腫瘤消除，及/或(d)腫瘤之長期疾病穩定（生長停滯）。在肺癌（諸如非小細胞肺癌）的治療中，治療有效量係減輕或消除咳嗽、呼吸急促、及/或疼痛的量。作為另一實例，CDK7抑制劑之有效量或治療有效量係導致CDK7蛋白活性減少之量。用於量測CDK7活性減少的方法對於所屬技術領域中具有通常知識者係已知的，且可藉由分析CDK7結合來判定，例如，如以下實例中所說明。For example, an effective amount of a compound is that amount that results in: (a) reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of tumors, and/or (d) ) long-term stable disease (growth arrest) of the tumor. In the treatment of lung cancer, such as non-small cell lung cancer, a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and/or pain. As another example, an effective or therapeutically effective amount of a CDK7 inhibitor is an amount that results in a decrease in CDK7 protein activity. Methods for measuring a reduction in CDK7 activity are known to those of ordinary skill in the art, and can be determined by assaying CDK7 binding, eg, as illustrated in the Examples below.

用於治療所需的式(I)之化合物或其醫藥上可接受之鹽的量將不僅隨著所選特定化合物或鹽而變化，且亦隨著投予途徑、所治療的疾病或病況之性質及/或症狀、及患者的年齡及病況而變化，而最終將由主治醫師或臨床醫師來決定。在投予醫藥上可接受之鹽的情況下，劑量可以游離鹼計算。所屬技術領域中具有通常知識者將理解，在某些情况下，可能需要以超過或甚至遠超過本文所述劑量範圍之量投予本文中所揭示之化合物，以有效及積極地治療特別是侵襲性疾病或病況。The amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, required for treatment will vary not only with the particular compound or salt selected, but also with the route of administration, the disease or condition being treated. nature and/or symptoms, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. Those of ordinary skill in the art will appreciate that in certain instances it may be desirable to administer the compounds disclosed herein in amounts exceeding or even far exceeding the dosage ranges described herein to effectively and aggressively treat, in particular, the aggressive disease or condition.

然而，通常，合適之劑量將常常在約0.05mg/kg至約10mg/kg之範圍內。例如，合適之劑量可在約0.10mg/kg至約7.5mg/kg體重/天，諸如約0.15mg/kg至約5.0mg/kg/接受者體重/天、約0.2mg/kg至約4.0mg/kg/接受者體重/天、或介於其間之任何量的範圍內。化合物可以單位劑型投予；例如，每單位劑型含有1至500mg、10至100mg、5至50mg、或介於其間之任何量的活性成分。In general, however, a suitable dosage will often be in the range of about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may be in the range of about 0.10 mg/kg to about 7.5 mg/kg body weight/day, such as about 0.15 mg/kg to about 5.0 mg/kg/recipient body weight/day, about 0.2 mg/kg to about 4.0 mg /kg/recipient body weight/day, or any amount in between. The compounds may be administered in unit dosage form; for example, each unit dosage form contains 1 to 500 mg, 10 to 100 mg, 5 to 50 mg, or any amount therebetween of the active ingredient.

所欲劑量可便利地以單一劑量呈現，或呈以適當間隔投予之分開劑量，例如，以每天二、三、四、或更多個亞劑量。亞劑量本身可進一步劃分成例如多次不連續的寬鬆間隔開投予。The desired dose may conveniently be presented in a single dose, or in divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-doses themselves may be further divided, for example, into discrete, loosely spaced administrations.

如所屬技術領域中具有通常知識者將顯而易知的，欲投予之有用體內劑量及特定投予模式將視年齡、體重、病痛嚴重性及所治療哺乳動物物種、所採用之特定化合物及所採用之這些化合物的特定用途而變化。有效劑量水準（即達到所欲效果所需之劑量水準）的判定可由所屬技術領域中具有通常知識者使用常規方法來達成，例如，人體臨床試驗、體內研究、及體外研究。例如，式(I)化合物、或其醫藥上可接受之鹽之有用劑量可藉由比較其體外活性及在動物模型中體內活性來判定。這種比較可藉由與已建立之藥物（諸如順鉑(cisplatin)及/或吉西他濱）比較來進行。As will be apparent to those of ordinary skill in the art, useful in vivo doses to be administered and the particular mode of administration will vary depending on the age, body weight, severity of affliction, and the species of mammal being treated, the particular compound employed, and The particular use for which these compounds are employed will vary. Determination of effective dosage levels (ie, dosage levels required to achieve the desired effect) can be achieved by those of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of compounds of formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity with in vivo activity in animal models. Such comparisons can be made by comparison with established drugs such as cisplatin and/or gemcitabine.

劑量及時間間隔可經個別地調節，以提供足以維持調節效應之活性部份之血漿水準或最小有效濃度(MEC)。各化合物之MEC將有所不同，但可自體內及/或體外數據估計。達成MEC所需之劑量將取決於個體特徵及投予途徑。然而，可使用HPLC檢定或生物檢定來判定血漿濃度。劑量時間間隔亦可使用MEC值來判定。組成物應使用維持血漿水準高於MEC達10至90%的時間、較佳地介於30至90%之間的時間且最佳的是介於50至90%之間的時間的方案投予。在局部投予或選擇性吸收之情況下，藥物之局部有效濃度可能與血漿濃度無關。Dosage and intervals may be adjusted individually to provide plasma levels or minimum effective concentration (MEC) of the active moiety sufficient to maintain a modulating effect. The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10 to 90% of the time, preferably between 30 to 90% of the time, and optimally between 50 to 90% of the time . In cases of local administration or selective uptake, the local effective concentration of the drug may not be related to plasma concentration.

應注意，主治醫師會瞭解如何及何時因毒性或器官功能異常而終止、中斷或調整投予。相反地，主治醫師亦會知道若臨床反應不充足（排除毒性），則將治療調整至較高水平。管理所關注病症時投予劑量之量值將隨所治療疾病或病況之嚴重性及投予途徑而異。疾病或病況之嚴重程度可例如部分地依據標準預後評估方法來評估。另外，劑量及可能的給藥頻率亦將根據個別患者之年齡、體重及反應而異。與以上討論之計畫類似的計畫可用於獸醫學。It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or abnormal organ function. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is insufficient (excluding toxicity). The magnitude of the dosage administered in the management of the condition of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of a disease or condition can be assessed, for example, based in part on standard prognostic assessment methods. In addition, the dosage and possibly the frequency of administration will also vary according to the age, weight and response of the individual patient. Programs similar to those discussed above are available in veterinary medicine.

可使用已知方法評估本文中所揭示之化合物、鹽、及組成物之療效及毒性。例如，特定化合物或共用某些化學部份之化合物亞組之毒物學可藉由判定對細胞系（例如哺乳動物且較佳人類細胞系）之體外毒性來建立。此類研究之結果通常可預測在動物（例如哺乳動物）或更具體而言在人類中之毒性。替代地，可使用已知方法判定動物模型（諸如小鼠、大鼠、兔、狗、或猴）中特定化合物之毒性。特定化合物之療效可使用數種公認方法（例如體外方法、動物模型或人體臨床試驗）來建立。當選擇模型來判定療效時，熟習此項技術者可由目前最佳技術的引導以選擇適當模型、劑量、投予途徑及/或方案。 實例 The efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subgroup of compounds sharing certain chemical moieties can be established by determining in vitro toxicity on cell lines, such as mammalian and preferably human cell lines. The results of such studies are generally predictive of toxicity in animals (eg, mammals) or, more specifically, humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models such as mice, rats, rabbits, dogs, or monkeys. The therapeutic effect of a particular compound can be established using several recognized methods such as in vitro methods, animal models or human clinical trials. When selecting a model to determine efficacy, one skilled in the art can be guided by the best current techniques to select the appropriate model, dose, route of administration and/or regimen. example

圖1繪示用於製造式(I)之化合物之合成方案。額外實施例在下列實例中進一步詳細揭示，其並非以任何方式意圖限制申請專利範圍之範圍。 中間物 17-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 Figure 1 depicts a synthetic scheme for the manufacture of compounds of formula (I). Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. Intermediate 1 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carbonitrile

中間物 1係根據公開程序(WO 2020/093006)來合成。 中間物 27-溴-3-(2,5-二氯嘧啶-4-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈（圖2） 7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1 H-吲哚-6-甲腈 Intermediate 1 was synthesized according to a published procedure (WO 2020/093006). Intermediate 2 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -indole- 6-carbonitrile (Figure 2) 7-Bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1 H -indole-6-carbonitrile

在密封管中，在室温下向2,4-二氯-5-硝基嘧啶(2.56g, 13.6mmol)於1,2-DCE (15mL)中之攪拌溶液添加AlCl 3(1.81g, 20.3mmol)，且在80℃下攪拌30min。接著在80℃下分批添加7-溴-1 H-吲哚-6-甲腈(1.000g, 4.524mmol)，並在80℃下攪拌12h。藉由TLC完成反應後，將反應混合物冷卻至0℃，並用冰水(30mL)淬滅，用10%於乙酸乙酯中之四氫呋喃(2 x 100mL)萃取。將合併之有機層用鹽水(50mL)洗滌，用Na 2SO 4乾燥，過濾並蒸發，以得到粗化合物。粗化合物用乙酸乙酯(100mL)研磨，並在真空下乾燥，以給出7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1 H-吲哚-6-甲腈（1.100g，2.906mmol，64%產率）。MS-(LCMS) m/z：C 13H 5BrClN 5O 2[M+H] +之計算值= 377.93/379.93，觀察值= 378.07/380.08。LCMS純度：94%； 1H NMR (400 MHz, DMSO- d 6 ) 13.13 (s, 1H), 9.32 (s, 1H), 8.31 (d, J= 2.8 Hz, 1H), 8.16 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H)。 7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-吲哚-6-甲腈 To a stirred solution of 2,4-dichloro-5-nitropyrimidine (2.56 g, 13.6 mmol) in 1,2-DCE (15 mL) was added AlCl 3 (1.81 g, 20.3 mmol) at room temperature in a sealed tube. ), and stirred at 80°C for 30min. Then 7-bromo- 1H -indole-6-carbonitrile (1.000g, 4.524mmol) was added in batches at 80°C and stirred at 80°C for 12h. After completion of the reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 10% THF in ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and evaporated to give crude compound. The crude compound was triturated with ethyl acetate (100 mL) and dried under vacuum to give 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl) -1H -indole-6- Formonitrile (1.100 g, 2.906 mmol, 64% yield). MS-( LCMS ) m/z : Calcd. for C13H5BrClN5O2 [M+H] + = 377.93 / 379.93 , observed = 378.07/380.08. LCMS purity: 94%; 1 H NMR (400 MHz, DMSO- d 6 ) 13.13 (s, 1H), 9.32 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H). 7-Bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6- Formaldehyde

在0℃下向7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1 H-吲哚-6-甲腈於DMF (30mL)之攪拌溶液(2.80g, 7.40mmol)添加NaH（60%於礦物油中，355mg，8.88mmol），攪拌10min，並於0℃下添加SEM-Cl (1.48g, 8.88mmol)。在0℃下將反應混合物攪拌3h。在藉由TLC消耗初始材料後，將反應混合物用冰水(50mL)淬滅，並用乙酸乙酯(2 x 100mL)萃取。分離合併之有機層，用Na 2SO 4乾燥並蒸發。將粗材料藉由矽膠(100-200)管柱層析法使用30至40%於石油醚（作為洗提液）中之EtOAc來純化，以給出7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1-((2(三甲基矽基)乙氧基)甲基)-1H-吲哚-6-甲腈（2.50g，4.91mmol，66%產率）。MS-(LCMS) m/z：C 19H 19BrClN 5O 3Si [M+H] +之計算值= 508.01/510.01，觀察值= 508.23/510.25。LCMS純度：93.28%； 1H NMR (400 MHz, CDCl 3) 8.99 (s, 1H), 8.39 (d, J= 8.4 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 5.97 (s, 2H), 3.60 (t, J= 8.0 Hz, 2H), 0.99 (t, J=8.0 Hz, 2H), 0.002 (s, 9H)。 3-(5-胺基-2-氯嘧啶-4-基)-7-溴-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈 To a stirred solution (2.80 g, 7.40 mmol) NaH (60% in mineral oil, 355 mg, 8.88 mmol) was added, stirred for 10 min, and SEM-Cl (1.48 g, 8.88 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were separated, dried over Na2SO4 and evaporated. The crude material was purified by column chromatography on silica gel (100-200) using 30 to 40% EtOAc in petroleum ether (as eluent) to give 7-bromo-3-(2-chloro- 5-nitropyrimidin-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.50g, 4.91mmol, 66% yield Rate). MS-(LCMS) m/z : Calcd . for C19H19BrClN5O3Si [M+H] + = 508.01 /510.01, observed = 508.23/510.25. LCMS purity: 93.28%; 1 H NMR (400 MHz, CDCl 3 ) 8.99 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J = 8.4 Hz , 1H), 5.97 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.99 (t, J =8.0 Hz, 2H), 0.002 (s, 9H). 3-(5-Amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -indole-6 -Formonitrile

向7-溴-3-(2-氯-5-硝基嘧啶-4-基)-1-((2(三甲基矽基)乙氧基)甲基)-1H-吲哚-6-甲腈(2.00g, 3.93mmol)於THF (20mL)及AcOH (5mL)中之攪拌溶液添加Fe粉末(2.195g, 39.31mmol)，並在室溫下攪拌16h。在藉由TLC消耗起始材料後，將反應混合物經由矽藻土床過濾，並用乙酸乙酯(50mL)洗滌，在減壓下蒸發得到粗產物，以水(30mL)稀釋，並用乙酸乙酯(2 x 750mL)萃取。分離有機層，用Na 2SO 4乾燥，過濾並蒸發。將粗產物用二***(25mL)研磨，以給出3-(5-胺基-2-氯嘧啶-4-基)-7-溴-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈（1.69g，3.54mmol，90%產率）。MS-(LCMS) m/z：C 19H 21BrClN 5OSi [M+H] +之計算值= 478.04/480.04，觀察值=478.25/480.22。LCMS純度：92.79%； 1H NMR (400 MHz, CDCl 3) 8.38 (d, J= 8.4 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.55 (d, J= 8.4 Hz, 1H), 5.97 (s, 2H), 3.88 (s, 2H, NH 2), 3.61 (t, J= 8.0 Hz, 2H), 0.95 (t, J= 8 Hz, 2H), 0.02 (s, 9H)。 7-溴-3-(2,5-二氯嘧啶-4-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈 To 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-indole-6- A stirred solution of carbonitrile (2.00 g, 3.93 mmol) in THF (20 mL) and AcOH (5 mL) was added Fe powder (2.195 g, 39.31 mmol) and stirred at room temperature for 16 h. After consumption of the starting material by TLC, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate (50 mL), evaporated under reduced pressure to give the crude product, diluted with water (30 mL), and washed with ethyl acetate ( 2 x 750mL) extraction. The organic layer was separated, dried over Na2SO4 , filtered and evaporated. The crude product was triturated with diethyl ether (25 mL) to give 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2-(trimethylsilyl)ethyl Oxy)methyl) -1H -indole-6-carbonitrile (1.69 g, 3.54 mmol, 90% yield). MS-(LCMS) m/z : Calcd. for C19H21BrClN5OSi [M+H] + = 478.04/ 480.04 , observed = 478.25 /480.22. LCMS purity: 92.79%; 1 H NMR (400 MHz, CDCl 3 ) 8.38 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.55 (d, J = 8.4 Hz , 1H), 5.97 (s, 2H), 3.88 (s, 2H, NH 2 ), 3.61 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8 Hz, 2H), 0.02 (s, 9H ). 7-Bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -indole-6-methanol Nitrile

於室溫下向3-(5-胺基-2-氯嘧啶-4-基)-7-溴-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈（三批，3 × 1.00g，3 × 2.09mmol）於ACN (20mL)中之攪拌溶液添加亞硝酸異戊酯(3 x 489mg, 3 x 4.18mmol)及Cu(I)Cl (414mg, 4.18mmol)，並在室溫下攪拌30min。在藉由TLC消耗起始材料後，將反應混合物用水(20mL)淬滅，用乙酸乙酯(2 x 70mL)萃取。分離合併之有機層，用Na 2SO 4乾燥並蒸發。將粗材料藉由矽膠(100-200)管柱層析法使用20至30%於石油醚（作為洗提液）中之EtOAc來純化，以給出7-溴-3-(2,5-二氯嘧啶-4-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈， 中間物 2（1.40g，2.82mmol，45%產率）。MS-(LCMS) m/z：C 19H 19BrCl 2N 4OSi [M+H] +之計算值= 496.99/498.99/500.98 (60%/100%/47%)，觀察值=497.21/499.23/501.20 (60%/100%/47%)。LCMS純度：96.23%； 1H NMR (400 MHz, CDCl 3) 8.76 (d, J= 8.4 Hz, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.58 (d, J= 8.4 Hz, 1H), 5.99 (s, 2H), 3.60 (t, J= 8.0 Hz, 2H), 0.95 (t, J= 8.0 Hz, 2H), -0.03 (s, 9H)。 中間物 37-溴-3-(6-鹵-2-(甲基磺醯基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈 To 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H at room temperature - To a stirred solution of indole-6-carbonitrile (three batches, 3 x 1.00 g, 3 x 2.09 mmol) in ACN (20 mL) was added isoamyl nitrite (3 x 489 mg, 3 x 4.18 mmol) and Cu( 1) Cl (414mg, 4.18mmol), and stirred at room temperature for 30min. After consumption of starting material by TLC, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (2 x 70 mL). The combined organic layers were separated, dried over Na2SO4 and evaporated. The crude material was purified by silica gel (100-200) column chromatography using 20 to 30% EtOAc in petroleum ether (as eluent) to give 7-bromo-3-(2,5- Dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -indole-6-carbonitrile, Intermediate 2 (1.40g, 2.82mmol , 45% yield). MS-(LCMS) m/z : Calcd. for C 19 H 19 BrCl 2 N 4 OSi [M+H] + = 496.99/498.99/500.98 (60%/100%/47%), observed = 497.21/499.23 /501.20 (60%/100%/47%). LCMS purity: 96.23%; 1 H NMR (400 MHz, CDCl 3 ) 8.76 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.58 (d, J = 8.4 Hz , 1H), 5.99 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H). Intermediate 3 7-bromo-3-(6-halo-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile

中間物 3係與 中間物 1類似地合成，其具有如(3,5-二氯-4-(三氟甲基)苯基)(甲基)硫烷、及(3-氯-5-氟-4-(三氟甲基)苯基)(甲基)硫烷之起始嘧啶類似物（參見WO 2005/047279、CN 112739689、及 J Fluorine Chemistry, 1987, 35,275-285），其接著氧化成碸。 中間物 43-(2-(甲基硫基)-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-羧酸 Intermediate 3 was synthesized analogously to Intermediate 1 with compounds such as (3,5-dichloro-4-(trifluoromethyl)phenyl)(methyl)sulfane, and (3-chloro-5-fluoro - the starting pyrimidine analog of 4-(trifluoromethyl)phenyl)(methyl)sulfane (see WO 2005/047279, CN 112739689, and J Fluorine Chemistry , 1987, 35, 275-285), followed by Oxidized to Phenol. Intermediate 4 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid

向3-(2-(甲基硫基)-5-(三氟甲基)嘧啶-4-基)-1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-6-甲腈（參考：WO 2019/143719）(0.900g, 1.89mmol)於EtOH (15mL)中之攪拌溶液添加5M NaOH水溶液(10mL)（在0℃下），並在70℃下攪拌16h。在反應完成後，將溶劑蒸發，並用2N HCl緩慢酸化至PH = ~4，並過濾沈澱物，且在真空下乾燥，以給出3-(2-(甲基硫基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3-b]吡啶-6-羧酸， 中間物 4（0.800g，未經純化之粗產物用於下一步驟）。MS-(LCMS) m/z：C 14H 9F 3N 4O 2S [M+H] +之計算值= 355.04，觀察值=355.14。 中間物 53-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈（圖3） 7-胺基-1H-吲哚-6-甲腈 To 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine - A stirred solution of 6-carbonitrile (ref: WO 2019/143719) (0.900 g, 1.89 mmol) in EtOH (15 mL) was added with 5M aqueous NaOH (10 mL) at 0 °C and stirred at 70 °C for 16 h . After the reaction was complete, the solvent was evaporated and slowly acidified with 2N HCl to pH = ~4, and the precipitate was filtered and dried under vacuum to give 3-(2-(methylthio)-5-(tri Fluoromethyl)pyrimidin-4-yl) -1H -pyrrolo[2,3-b]pyridine-6-carboxylic acid, intermediate 4 (0.800 g, the crude product was used in the next step without purification). MS-(LCMS) m/ z : Calcd . for C14H9F3N4O2S [M+H] + = 355.04 , observed = 355.14. Intermediate 5 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxoisotetrahydrothiazol-2-yl)-1 H -indole -6-carbonitrile (Figure 3) 7-Amino-1H-indole-6-carbonitrile

在密封管中，向7-溴-1 H-吲哚-6-甲腈（參考WO 2018/013867，三批，3 × 3.000g，3 × 13.57mmol）於NMP(30mL)及水(10mL)中之攪拌溶液添加NaN 3(3 x 3.529g, 3 x 54.28mmol)、抗壞血酸鈉(5.377g, 27.14mmol)，並用氬除氣10min。隨後添加CuI (3 x 517mg, 3 x 2.71mmol)、及( S, S’)- N, N’-二甲基-1,2 -環己烷二胺(3 x 642µL, 3 x 4.07mmol)，再次除氣10min。將反應混合物在100℃下加熱2h。在反應完成後，將反應冷卻至室溫，並在減壓下蒸發溶劑。將棕色殘餘物用EtOAc (100mL)稀釋，使其通過矽藻土墊，並用EtOAc (100mL)洗滌。將濾液在減壓下蒸發，並將粗產物藉由矽膠管柱層析法使用20至30% EtOAc及石油醚來純化，以給出7-胺基-1H-吲哚-6-甲腈(3.62g , 23.0mmol, 57%)。MS-(LCMS) m/z：C 9H 7N 3[M+H] +之計算值=158.06，觀察值=158.26。 1H NMR (400 MHz, CDCl 3) δ 8.43 (br s, 1H, NH), 7.32 (dd, J= 3.0, 3.0 Hz, 1H), 7.11 (s, 2H), 6.57 (dd, J= 2.2, 3.0 Hz, 1H), 4.45 (br s, 2H, NH 2)。 3-氯- N-(6-氰基-1 H-吲哚-7-基)丙烷-1-磺醯胺 In a sealed tube, add 7-bromo- 1H -indole-6-carbonitrile (refer to WO 2018/013867, three batches, 3 × 3.000g, 3 × 13.57mmol) in NMP (30mL) and water (10mL) The stirred solution in was added NaN3 (3 x 3.529g, 3 x 54.28mmol), sodium ascorbate (5.377g, 27.14mmol) and degassed with argon for 10min. CuI (3 x 517 mg, 3 x 2.71 mmol), and ( S , S' )- N , N' -dimethyl-1,2-cyclohexanediamine (3 x 642 µL, 3 x 4.07 mmol) were then added , degas again for 10 minutes. The reaction mixture was heated at 100 °C for 2 h. After completion of the reaction, the reaction was cooled to room temperature, and the solvent was evaporated under reduced pressure. The brown residue was diluted with EtOAc (100 mL), passed through a pad of Celite, and washed with EtOAc (100 mL). The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using 20 to 30% EtOAc and petroleum ether to give 7-amino-1H-indole-6-carbonitrile ( 3.62g, 23.0mmol, 57%). MS-(LCMS) m/z : Calcd. for C9H7N3 [ M+H] + = 158.06 , observed = 158.26. 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (br s, 1H, NH), 7.32 (dd, J = 3.0, 3.0 Hz, 1H), 7.11 (s, 2H), 6.57 (dd, J = 2.2, 3.0 Hz, 1H), 4.45 (br s, 2H, NH 2 ). 3-Chloro- N- (6-cyano-1 H -indol-7-yl)propane-1-sulfonamide

在0℃下向7-胺基-1H-吲哚-6-甲腈(2.80g, 17.8mmol)於DCM (20mL)中之攪拌溶液添加吡啶(2.87mL, 35.6mmol)、DMAP (1.74g, 14.3mmol)、及3-氯丙烷-1-磺醯氯化物(10.8mL, 89.1mmol)（分批），並在室溫下攪拌16h。藉由TLC消耗起始材料後，將反應混合物用冷水(50mL)淬滅，用DCM (2 x 75mL)萃取。分離合併之有機層，用Na 2SO 4乾燥並蒸發。將所得粗材料藉由矽膠(100-200)管柱層析法使用20%至30%於石油醚中之EtOAc來純化，以給出3-氯- N-(6-氰基-1 H-吲哚-7-基)丙烷-1-磺醯胺（3.51g，11.8mmol，66%產率）。MS-(LCMS) m/z：C 12H 12ClN 3O 2S [M+H] +之計算值= 298.03，觀察值= 298.24。 7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈 To a stirred solution of 7-amino-1H-indole-6-carbonitrile (2.80 g, 17.8 mmol) in DCM (20 mL) was added pyridine (2.87 mL, 35.6 mmol), DMAP (1.74 g, 14.3mmol), and 3-chloropropane-1-sulfonyl chloride (10.8mL, 89.1mmol) (partitions), and stirred at room temperature for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold water (50 mL), extracted with DCM (2 x 75 mL). The combined organic layers were separated, dried over Na2SO4 and evaporated. The resulting crude material was purified by column chromatography on silica gel (100-200) using 20% to 30% EtOAc in petroleum ether to give 3-chloro- N- (6-cyano- 1H- Indol-7-yl)propane-1-sulfonamide (3.51 g, 11.8 mmol, 66% yield). MS- ( LCMS) m/z : Calcd . for C12H12ClN3O2S [ M +H] + = 298.03, observed = 298.24. 7-(1,1-Dioxoisotetrahydrothiazol-2-yl)-1 H -indole-6-carbonitrile

在0℃下向3-氯- N-(6-氰基-1 H-吲哚-7-基)丙烷-1-磺醯胺(3.50g, 11.8mmol)於DMF (35mL)中之攪拌溶液添加DBU (5.27mL, 35.3mmol)，在室溫下攪拌16h。藉由TLC消耗起始材料後，將反應混合物用冷水(100mL)淬滅，用乙酸乙酯(2 x 150mL)萃取。分離合併之有機層，用Na 2SO 4乾燥並蒸發。使所得粗材料藉由矽膠(100-200)管柱層析法使用20%至30%於石油醚中之EtOAc來純化，以給出7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈（2.61g，9.962mmol，85%產率）。MS-(LCMS) m/z：C 11H 11N 3O 2S [M+H] +之計算值= 262.06，觀察值= 262.30。 1H NMR (400 MHz, DMSO- d 6 ) δ 11.63 (br s, 1H, NH), 7.76 (d, J= 8.0 Hz, 1H), 7.11 (dd, J= 2.8, 2.8 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 6.67 (dd, J= 2.0, 2.8 Hz, 1H), 3.86 (t, J= 6.4 Hz, 2H), 3.56 (t, J= 7.2 Hz, 2H), 2.63-2.56 (m, 2H)。 3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈 To a stirred solution of 3-chloro- N- (6-cyano- 1H -indol-7-yl)propane-1-sulfonamide (3.50g, 11.8mmol) in DMF (35mL) at 0°C Add DBU (5.27mL, 35.3mmol) and stir at room temperature for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold water (100 mL), extracted with ethyl acetate (2 x 150 mL). The combined organic layers were separated, dried over Na2SO4 and evaporated. The resulting crude material was purified by column chromatography on silica gel (100-200) using 20% to 30% EtOAc in petroleum ether to give 7-(1,1-dioxoisotetrahydrothiazole- 2-yl) -1H -indole-6-carbonitrile (2.61 g, 9.962 mmol, 85% yield). MS- ( LCMS) m/z : Calcd . for C11H11N3O2S [M+H] + = 262.06 , observed = 262.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.63 (br s, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 2.8, 2.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 2.0, 2.8 Hz, 1H), 3.86 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.63 -2.56 (m, 2H). 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxoisotetrahydrothiazol-2-yl)-1 H -indole-6- Formaldehyde

在密封管中，於室溫下向2,4-二氯-5-(三氟甲基)嘧啶(3.737g, 17.22mmol)於1,2-DCE (15mL)中之攪拌溶液添加AlCl 3(1.378g, 10.33mmol)，並在80℃下攪拌30min。隨後在80℃下添加7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈(900mg, 3.44mmol)，並在80℃下攪拌16h。在藉由TLC完成反應後，將反應混合物冷卻至0℃，且用冰水(30mL)淬滅，用2-甲基四氫呋喃(2 x 150mL)萃取。將合併之有機層用鹽水(50mL)洗滌，用Na 2SO 4乾燥，過濾並蒸發，以得到粗化合物。粗化合物藉由矽膠管柱層析法使用20%至30%於石油醚（作為移動相）中之EtOAc來純化，以給出3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈（ 中間物 5）之部分純化化合物，其藉由製備型HPLC純化以給出 中間物 5（590mg，1.34mmol，39%產率）。MS-(LCMS) m/z：C 17H 11ClF 3N 5O 2S [M+H] +之計算值= 442.03，觀察值= 442.35。 1H NMR (400 MHz, DMSO- d 6 ) δ 12.62 (br s, 1H, NH), 9.16 (s, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.21 (s, 1H), 7.71 (d, J= 8.4 Hz, 1H), 3.92 (t, J= 6.8 Hz, 2H), 3.61 (t, J= 7.2 Hz, 2H), 2.67-2.60 (m, 2H)。 中間物 63-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代-1,2-噻嗪-2-基)-1 H-吲哚-6-甲腈 To a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.737 g, 17.22 mmol) in 1,2-DCE (15 mL) was added AlCl 3 ( 1.378g, 10.33mmol), and stirred at 80°C for 30min. Then 7-(1,1-dioxoisotetrahydrothiazol-2-yl)-1 H -indole-6-carbonitrile (900mg, 3.44mmol) was added at 80°C and stirred at 80°C for 16h . After completion of the reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 2-methyltetrahydrofuran (2 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and evaporated to give crude compound. The crude compound was purified by silica gel column chromatography using 20% to 30% EtOAc in petroleum ether (as mobile phase) to give 3-(2-chloro-5-(trifluoromethyl)pyrimidine- Partially purified compound of 4-yl)-7-(1,1-dioxoisotetrahydrothiazol-2-yl) -1H -indole-6-carbonitrile ( intermediate 5 ), which was obtained by preparative HPLC purification to give intermediate 5 (590 mg, 1.34 mmol, 39% yield). MS-(LCMS) m/z : Calcd . for C17H11ClF3N5O2S [M+H] + = 442.03 , observed = 442.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.62 (br s, 1H, NH), 9.16 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.67-2.60 (m, 2H). Intermediate 6 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxo-1,2-thiazin-2-yl)-1 H -Indole-6-carbonitrile

中間物 6係與 中間物 5類似地合成。MS-(LCMS) m/z：C 18H 13ClF 3N 5O 2S [M+H] +之計算值= 456.04，觀察值= 456.37。 1H NMR及19F-HOESY] +。 1H NMR (400 MHz, DMSO- d 6 ) δ 12.44 (brs, 1H, NH), 9.14 (s, 1H), 8.35 (d, J= 8.4 Hz, 1H), 8.16 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.76 – 3.73 (m, 1H), 3.48 – 3.32 (m, 1H), 2.40 – 2.23 (m, 2H), 2.01 – 1.83 (m, 2H)。 中間物 7磷烷1-氧化物 Intermediate 6 was synthesized similarly to Intermediate 5 . MS- ( LCMS) m/z : Calcd . for C18H13ClF3N5O2S [ M +H] + = 456.04 , observed = 456.37. 1 H NMR and 19F-HOESY] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.44 (brs, 1H, NH), 9.14 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.65 ( d, J = 8.4 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.76 – 3.73 (m, 1H), 3.48 – 3.32 (m, 1H), 2.40 – 2.23 (m, 2H), 2.01 – 1.83 ( m, 2H). Intermediate 7 Phosphine 1-Oxide

在0℃下將1,4-二溴丁烷(2.000g, 9.263mmol)於THF (5mL)中的溶液添加入活化鎂(0.474g, 19.5mmol)於THF (5mL)中，並在0℃下攪拌1.5h。接著在0℃下將亞磷酸二乙酯(0.61mL, 4.8mmol)於THF (2mL)中的溶液添加至反應混合物中，並在室溫下攪拌16h。在藉由監測TLC消耗起始材料後，該反應混合物係用NH 4Cl水溶液(20mL)淬滅且經由矽藻土床來過濾，用DCM (10mL)洗滌。將經分離之有機層用Na 2SO 4乾燥，過濾並在35℃下蒸發，以給出呈淡黃色膠狀液體之磷烷1-氧化物（中間物1（0.300g，2.88mmol，粗產物）），且其不經進一步純化及分析就用於下一步驟。（參考文獻： J. Molecular Catalysis A: Chemical, 2000, 160 (2),249） 中間物 8磷 1-氧化物 A solution of 1,4-dibromobutane (2.000g, 9.263mmol) in THF (5mL) was added into activated magnesium (0.474g, 19.5mmol) in THF (5mL) at 0°C, and at 0°C Under stirring for 1.5h. Then a solution of diethylphosphite (0.61 mL, 4.8 mmol) in THF (2 mL) was added to the reaction mixture at 0 °C and stirred at room temperature for 16 h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with aqueous NH 4 Cl (20 mL) and filtered through a bed of Celite, washing with DCM (10 mL). The separated organic layer was dried over Na2SO4 , filtered and evaporated at 35 °C to give phosphine 1-oxide (Intermediate 1 (0.300 g, 2.88 mmol, crude product )), and it was used in the next step without further purification and analysis. (Reference: J. Molecular Catalysis A: Chemical , 2000 , 160 (2), 249) Intermediate 8 Phosphorus 1-oxide

中間物 8係與 中間物 7類似地合成。 實例 13-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈（圖4） Intermediate 8 was synthesized analogously to Intermediate 7 . Example 1 3-(2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-( 1-oxophosphorane-1-yl) -1H -indole-6-carbonitrile (Figure 4)

向7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈（ 中間物 1，WO 2020/093006）(590mg, 1.47mmol)於NMP (6mL)中之攪拌溶液添加DIPEA (1.28mL, 7.35mmol)及苄基(2 S,5 S)-5-胺基-2-甲基哌啶-1-羧酸酯HCl鹽(420mg, 1.47mmol)，並在140℃下攪拌16h。在藉由監測TLC消耗起始材料後，將反應混合物用水(50mL)淬滅，用乙酸乙酯(2 x 50mL)萃取。分離合併之有機層，用Na 2SO 4乾燥，過濾並蒸發。將粗產物藉由矽膠(100-200)管柱層析法使用20至30%於石油醚中之EtOAc來純化，以給出苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（750mg，1.22mmol，83%產率）。MS-(LCMS) m/z：C 28H 24BrF 3N 6O 2[M+H] +之計算值= 613.11/615.11，觀察值= 613.16/615.14。 To 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carbonitrile ( Intermediate 1 , WO 2020/093006) (590mg, 1.47 mmol) in NMP (6 mL) was added DIPEA (1.28 mL, 7.35 mmol) and benzyl ( 2S , 5S )-5-amino-2-methylpiperidine-1-carboxylate HCl salt (420mg, 1.47mmol), and stirred at 140°C for 16h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layers were separated, dried over Na2SO4 , filtered and evaporated. The crude product was purified by silica gel (100-200) column chromatography using 20 to 30% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((4-( 7-Bromo-6-cyano- 1H -indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate (750 mg, 1.22 mmol, 83% yield). MS-(LCMS) m/z : Calcd. for C28H24BrF3N6O2 [M+H ] + = 613.11 /615.11, observed = 613.16 /615.14.

在微波小瓶中，向苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（三批，3 × 100mg，0.163mmol）於DMF (1mL)中之經氬除氣溶液添加磷烷1-氧化物、 中間物 7(3 x 339mg, 3 x 3.26mmol)、K 3PO 4(3 x 38mg, 3 x 0.18mmol)、xanthphos (3 x 9.3mg, 3 x 0.016mmol)、及Pd(OAc) 2(3 x 3.6mg, 3 x 0.016mmol)。將反應混合物在微波中在150℃下加熱1h。在藉由監測TLC消耗起始材料後，將反應混合物用水(10mL)淬滅，並用乙酸乙酯(2 x 10mL)萃取。將粗化合物藉由矽膠(100-200)管柱層析法使用50至60%於石油醚中之EtOAc（作為移動相）來純化，以給出苄基(2 S,5 S)-5-((4-(6-氰基-7-(1-氧代磷烷-1-基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基-哌啶-1-羧酸酯（85mg，用於3批，0.13mmol，27%產率），其呈淺黃色黏性液體。MS (LCMS) m/z：C 32H 32F 3N 6O 3P [M+H] +之計算值= 637.22，觀察值= 637.42。 Benzyl( 2S , 5S )-5-((4-(7-bromo-6-cyano- 1H -indol-3-yl)-5-(trifluoromethyl )pyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate (three batches, 3 x 100 mg, 0.163 mmol) in DMF (1 mL) degassed with argon was added phosphine 1 -oxide, intermediate 7 (3 x 339mg, 3 x 3.26mmol), K 3 PO 4 (3 x 38mg, 3 x 0.18mmol), xanthphos (3 x 9.3mg, 3 x 0.016mmol), and Pd(OAc ) 2 (3 x 3.6mg, 3 x 0.016mmol). The reaction mixture was heated in microwave at 150 °C for 1 h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The crude compound was purified by column chromatography on silica gel (100-200) using 50 to 60% EtOAc in petroleum ether as mobile phase to give benzyl ( 2S , 5S )-5- ((4-(6-cyano-7-(1-oxophosphoran-1-yl)-1 H -indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)-2-methyl-piperidine-1-carboxylate (85 mg, for 3 batches, 0.13 mmol, 27% yield) as pale yellow viscous liquid. MS ( LCMS) m/z : Calcd . for C32H32F3N6O3P [M+H] + = 637.22 , observed = 637.42.

向苄基(2 S,5 S)-5-((4-(6-氰基-7-(1-氧代磷烷-1-基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基-哌啶-1-羧酸酯(150mg, 0.236mmol)於乙酸乙酯(2mL)中之攪拌溶液添加10%鈀碳（50%水分）(70mg)，並在氫氣球氛圍下、室溫下攪拌3天。在藉由監測TLC反應完成後，將反應混合物經由矽藻土床過濾，並用乙酸乙酯洗滌。濃縮濾液以得到粗材料，其藉由製備型HPLC純化，以給出3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈， 實例 1(36.8mg, 0.0732mmol, 31%)。 To benzyl (2 S ,5 S )-5-((4-(6-cyano-7-(1-oxophosphoran-1-yl)-1 H -indol-3-yl)-5 A stirred solution of -(trifluoromethyl)pyrimidin-2-yl)amino)-2-methyl-piperidine-1-carboxylate (150 mg, 0.236 mmol) in ethyl acetate (2 mL) was added 10% palladium carbon (50% moisture) (70 mg), and stirred at room temperature under a hydrogen balloon atmosphere for 3 days. After completion of the reaction was monitored by TLC, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The filtrate was concentrated to give crude material, which was purified by preparative HPLC to give 3-(2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyrimidin-4-yl)-7-(1-oxophosphoran-1-yl) -1H -indole-6-carbonitrile, Example 1 (36.8mg, 0.0732mmol, 31% ).

製備型HPLC方法：管柱/尺寸：X-橋苯基(19*250*5µm)；移動相A：水中之10 mm碳酸氫銨；移動相B：乙腈梯度（時間/%B）：0.01/30、1/30、10/55、14/59、14.1/100、17/100、20 /30、20.1/30。流速：18ml/min溶解度：乙腈+THF+水。Preparative HPLC method: column/size: X-endophenyl (19*250*5µm); mobile phase A: 10 mm ammonium bicarbonate in water; mobile phase B: acetonitrile gradient (time/%B): 0.01/ 30, 1/30, 10/55, 14/59, 14.1/100, 17/100, 20/30, 20.1/30. Flow rate: 18ml/min Solubility: acetonitrile+THF+water.

MS-(LCMS) m/z：C 24H 26F 3N 6OP [M+H] +之計算值= 503.19，觀察值= 503.52。 1H NMR (400 MHz, , 90℃ VT, DMSO- d 6 ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.61 (dd, J = 3.0, 8.4 Hz 1H), 7.43 (d, J= 8.4 Hz, 1H, NH), 3.92 – 3.78 (m, 1H), 3.20 – 3.13 (m, 1H), 2.50 – 2.58 (m, 1H), 2.45 – 2.35 (m, 3H), 2.30 – 2.07 (m, 6H), 2.07 – 1.95 (m, 1H), 1.71 – 1.64 (m, 1H), 1.55 – 1.39 (m, 1H), 1.18 – 1.06 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H)。LCMS純度：98.47%；HPLC純度：99.36%。 MS-(LCMS) m/z : Calcd . for C24H26F3N6OP [M+H] + = 503.19 , observed = 503.52. 1 H NMR (400 MHz, , 90℃ VT, DMSO- d 6 ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.61 (dd, J = 3.0, 8.4 Hz 1H), 7.43 (d, J = 8.4 Hz, 1H, NH), 3.92 – 3.78 (m, 1H), 3.20 – 3.13 (m, 1H), 2.50 – 2.58 (m, 1H), 2.45 – 2.35 (m, 3H), 2.30 – 2.07 (m, 6H), 2.07 – 1.95 (m, 1H), 1.71 – 1.64 (m, 1H), 1.55 – 1.39 (m, 1H), 1.18 – 1.06 (m, 1H ), 0.98 (d, J = 6.0 Hz, 3H). LCMS purity: 98.47%; HPLC purity: 99.36%.

於 表 2中之實例係使用與針對 實例 1之合成所述相似之方法來製備。 表 2 實例編號 結構 名稱 質量離子計算值 / 觀測值 2 3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷 -1-基)-1 H-吲哚-6-甲腈 517.20/515.30 3 ( S)-3-(2-((6,6-二甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6 -甲腈 517.20/517.31 4 ( S)-7-(1-氧代磷烷-1-基)-3-(2-(哌啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 489.17/489.51 5 7-(1-氧代磷烷-1-基)-3-(2-(哌啶-4-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 488.17/489.50 6 ( S)-7-(1-氧代磷烷-1-基)-3-(2-(吡咯啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 475.15/475.28 7 3-(2-(((1 S,2 S)-2-(乙基胺基)環戊基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 515.20/515.34 實例 83-(5-氯-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈（圖5） The examples in Table 2 were prepared using methods similar to those described for the synthesis of Example 1 . table 2 instance number structure name Mass ion calculated value / observed value 2 3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1- Oxophosphorus -1-yl)-1 H -indole-6-carbonitrile 517.20/515.30 3 ( S )-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1-oxo Phosphalan-1-yl)-1 H -indole-6-carbonitrile 517.20/517.31 4 ( S )-7-(1-oxophosphorane-1-yl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H -indole-6-carbonitrile 489.17/489.51 5 7-(1-oxophosphorane-1-yl)-3-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -ind Indole-6-carbonitrile 488.17/489.50 6 ( S )-7-(1-oxophosphorane-1-yl)-3-(2-(pyrrolidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H -indole-6-carbonitrile 475.15/475.28 7 3-(2-(((1 S ,2 S )-2-(ethylamino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1 -Oxophosphorane-1-yl)-1 H -indole-6-carbonitrile 515.20/515.34 Example 8 3-(5-chloro-2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxophosphorus Alk-1-yl) -1H -indole-6-carbonitrile (Figure 5)

向苄基(2 S,5 S)-5-胺基-2-甲基哌啶-1-羧酸酯HCl鹽(0.689g, 2.42mmol)於1,4-二 烷(12mL)中之攪拌溶液添加DIPEA (2.10mL, 12.1mmol)，隨後添加 中間物 2(1.21g, 2.42mmol)，並在120℃下攪拌16h。在起始材料消耗後，將反應混合物在減壓下蒸發，以得到粗化合物。將粗產物藉由矽膠(100-200)管柱層析法使用20至30%於石油醚中之EtOAc來純化，以給出苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-3-基)-5-氯嘧啶-2-基)胺基)-2-甲基-哌啶-1-羧酸酯（0.8g，1.13mmol，47%產率）。MS (LCMS) m/z：C 33H 38BrClN 6O 3Si [M+H] +之計算值= 709.16/711.16/712.17 (75%/100%/36%)，觀察值= 709.53/711.54/712.56 (71%/100%/36%)。LCMS純度：93.35%； 1H NMR (400 MHz, CDCl 3) δ 8.53 (d, J= 8.4 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.35 – -7.25 (bs, 5H), 5.99 (s, 2H), 5.54 (d, J= 7.6 Hz, 1H), 5.18-5.09 (m, 2H), 4.64 – 4.54 (m, 1H), 4.32 (d, J= 14.0 Hz, 1H), 4.25-4.13 (m, 1H), 3.63 (t, J= 8.0 Hz, 2H), 3.26 (dd, J= 2.4, 14 Hz, 1H), 2.10 – 1.90 (m, 2H), 1.53 – 1.44 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 0.98 (t, J= 8.0 Hz, 2H), 0.00 (s, 9H)。 Benzyl (2 S ,5 S )-5-amino-2-methylpiperidine-1-carboxylate HCl salt (0.689g, 2.42mmol) in 1,4-bis A stirred solution in alkanes (12 mL) was added DIPEA (2.10 mL, 12.1 mmol) followed by Intermediate 2 (1.21 g, 2.42 mmol) and stirred at 120 °C for 16 h. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel (100-200) column chromatography using 20 to 30% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((4-( 7-Bromo-6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -indol-3-yl)-5-chloropyrimidin-2-yl) Amino)-2-methyl-piperidine-1-carboxylate (0.8 g, 1.13 mmol, 47% yield). MS (LCMS) m/z : Calcd. for C 33 H 38 BrClN 6 O 3 Si [M+H] + = 709.16/711.16/712.17 (75%/100%/36%), observed = 709.53/711.54/ 712.56 (71%/100%/36%). LCMS purity: 93.35%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 – -7.25 (bs, 5H), 5.99 (s, 2H), 5.54 (d, J = 7.6 Hz, 1H), 5.18-5.09 (m, 2H), 4.64 – 4.54 (m, 1H ), 4.32 (d, J = 14.0 Hz, 1H), 4.25-4.13 (m, 1H), 3.63 (t, J = 8.0 Hz, 2H), 3.26 (dd, J = 2.4, 14 Hz, 1H), 2.10 – 1.90 (m, 2H), 1.53 – 1.44 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 0.98 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H).

向苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-3-基)-5-氯嘧啶-2-基)胺基)-2-甲基-哌啶-1-羧酸酯（二批，2 × 0.400g，0.563mmol）於THF (4mL)中之攪拌溶液添加乙二胺(2 x 0.11mL, 2 x 1.69mmol)及TBAF (2 x 3.38mL, 2 x 3.38mmol)。在70℃下將反應混合物攪拌1h。在藉由TLC消耗初始材料後，將反應混合物用水(50mL)淬滅，並用乙酸乙酯(2 x 50mL)萃取。分離合併之有機層，用Na 2SO 4乾燥，過濾並蒸發。將粗產物藉由矽膠(100-200)管柱層析法使用40至50%於石油醚中之EtOAc來純化，以給出苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1 H-吲哚-3-基)-5-氯嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（0.570g，0.983mmol，87%產率）。MS-(LCMS) m/z：C 27H 24BrClN 6O 2[M+H] +之計算值= 579.08/581.08/582.08 (77%/100%/31%)，觀察值= 579.19/581.21/583.20 (77%/100%/30%)。LCMS純度：98.85%； 1H NMR (400 MHz, CDCl 3) δ 9.14 (s, 1H, NH), 8.49 (d, J=8.4 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.34 – 7.20 (bs, 5H), 5.48 (d, J= 7.2 Hz, 1H, NH), 5.15 – 5.07 (m, 2H), 4.62 – 4.56 (m, 1H), 4.32 (d, J= 14.0 Hz, 1H), 4.23 – 4.14 (m, 1H), 3.24 (dd, J= 2.4, 14.0 Hz, 1H), 2.06 – 1.91 (m, 2H), 1.50 – 1.42 (m, 1H), 1.24 (d, J=6.8 Hz, 3H)。 To benzyl (2 S ,5 S )-5-((4-(7-bromo-6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -indol-3-yl)-5-chloropyrimidin-2-yl)amino)-2-methyl-piperidine-1-carboxylate (two batches, 2 × 0.400g, 0.563mmol) in THF ( 4 mL) was added ethylenediamine (2 x 0.11 mL, 2 x 1.69 mmol) and TBAF (2 x 3.38 mL, 2 x 3.38 mmol). The reaction mixture was stirred at 70 °C for 1 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were separated, dried over Na2SO4 , filtered and evaporated. The crude product was purified by column chromatography on silica gel (100-200) using 40 to 50% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((4-( 7-bromo-6-cyano- 1H -indol-3-yl)-5-chloropyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate (0.570g, 0.983 mmol, 87% yield). MS-(LCMS) m/z : Calcd. for C 27 H 24 BrClN 6 O 2 [M+H] + = 579.08/581.08/582.08 (77%/100%/31%), observed = 579.19/581.21/ 583.20 (77%/100%/30%). LCMS purity: 98.85%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H, NH), 8.49 (d, J =8.4 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H ), 7.47 (d, J = 8.4 Hz, 1H), 7.34 – 7.20 (bs, 5H), 5.48 (d, J = 7.2 Hz, 1H, NH), 5.15 – 5.07 (m, 2H), 4.62 – 4.56 ( m, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.23 – 4.14 (m, 1H), 3.24 (dd, J = 2.4, 14.0 Hz, 1H), 2.06 – 1.91 (m, 2H), 1.50 – 1.42 (m, 1H), 1.24 (d, J =6.8 Hz, 3H).

在微波小瓶中，向苄基(2 S,5 S)-5-((4-(7-溴-6-氰基-1 H-吲哚-3-基)-5-氯嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（五批，5 × 100mg，5 × 0.172mmol）於DMF (1mL)中之經氬除氣溶液添加磷烷1-氧化物、 中間物 7(5 x 359mg, 5 x 3.45mmol)、K 3PO 4(5 x 40mg, 5 x 0.19mmol)、xantphos (5 x 10mg, 5 x 0.017mmol)、及Pd(OAc) 2(3.9mg, 5 x 0.017mmol)，在微波反應器中於150℃下攪拌1h。在起始材料消耗後，將反應混合物用水(20mL)淬滅，並用乙酸乙酯(3 x 25mL)萃取。將合併之有機層用Na 2SO 4乾燥並蒸發，以得到粗材料。將粗化合物藉由矽膠管柱層析法使用90至100%於石油醚中之EtOAc純化，以給出苄基(2 S,5 S)-5-((5-氯-4-(6-氰基-7-(1-氧代磷烷-1-基)-1 H-吲哚-3-基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯， 中間物 9（180mg，0.298mmol，35%產率）。MS-(LCMS) m/z：C 31H 32ClN 6O 3P [M+H] +之計算值= 603.20，觀察值= 603.55。LCMS純度：94.25%； 1H NMR (400 MHz, CDCl 3) δ 12.02 (s, 1H, NH), 8.74 (d, J= 8.0 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 7.58 (dd, J=3.2, 8.0 Hz, 1H), 7.34 –7.20 (bs, 5H), 5.47 (d, J= 7.2 Hz, 1H), 5.16 – 5.05 (m, 2H), 4.62 – 4.52 (m, 1H), 4.31 (d, J= 14.0 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.23 (dd, J= 2.4, 14.0 Hz, 1H), 2.50 – 2.17 (m, 8H), 2.10 – 1.87 (m, 2H), 1.50 – 1.40 (m, 1H), 1.24 (d, J =6.8 Hz, 3H)。 In a microwave vial, add benzyl( 2S , 5S )-5-((4-(7-bromo-6-cyano- 1H -indol-3-yl)-5-chloropyrimidine-2- To an argon-degassed solution of (1)amino)-2-methylpiperidine-1-carboxylate (five batches, 5 x 100 mg, 5 x 0.172 mmol) in DMF (1 mL) was added phosphine 1-oxide , Intermediate 7 (5 x 359mg, 5 x 3.45mmol), K 3 PO 4 (5 x 40mg, 5 x 0.19mmol), xantphos (5 x 10mg, 5 x 0.017mmol), and Pd(OAc) 2 (3.9 mg, 5 x 0.017mmol), stirred at 150 °C for 1 h in a microwave reactor. After the starting material was consumed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated to give crude material. The crude compound was purified by silica gel column chromatography using 90 to 100% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((5-chloro-4-(6- Cyano-7-(1-oxophosphoran-1-yl) -1H -indol-3-yl)pyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate , Intermediate 9 (180 mg, 0.298 mmol, 35% yield). MS- ( LCMS) m/z : Calcd. for C31H32ClN6O3P [M+H] + = 603.20 , observed = 603.55. LCMS purity: 94.25%; 1 H NMR (400 MHz, CDCl 3 ) δ 12.02 (s, 1H, NH), 8.74 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H ), 7.58 (dd, J =3.2, 8.0 Hz, 1H), 7.34 –7.20 (bs, 5H), 5.47 (d, J = 7.2 Hz, 1H), 5.16 – 5.05 (m, 2H), 4.62 – 4.52 ( m, 1H), 4.31 (d, J = 14.0 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.23 (dd, J = 2.4, 14.0 Hz, 1H), 2.50 – 2.17 (m, 8H), 2.10 – 1.87 (m, 2H), 1.50 – 1.40 (m, 1H), 1.24 (d, J =6.8 Hz, 3H).

向 中間物 9（二批，2 × 40mg，0.066mmol）於DCM (0.4mL)中之攪拌溶液添加Et 3N (2 x 4µL, 2 x 0.03mmol)、Et 3SiH (2 x 53µL, 2 x 39mg, 2 x 0.33mmol)、Pd(OAc) 2(2 x 3.0mg, 2 x 0.013mmol)，並在室溫下攪拌1.5h。在起始材料消耗後，將反應混合物在減壓下蒸發。將粗化合物藉由製備型HPLC純化，以給出3-(5-氯-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈， 實例 8（18mg，0.038mmol，29%產率）。 To a stirred solution of Intermediate 9 (two batches, 2 x 40 mg, 0.066 mmol) in DCM (0.4 mL) was added Et 3 N (2 x 4 µL, 2 x 0.03 mmol), Et 3 SiH (2 x 53 µL, 2 x 39 mg, 2 x 0.33 mmol), Pd(OAc) 2 (2 x 3.0 mg, 2 x 0.013 mmol), and stirred at room temperature for 1.5 h. After the starting material was consumed, the reaction mixture was evaporated under reduced pressure. The crude compound was purified by preparative HPLC to give 3-(5-chloro-2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)pyrimidine-4- yl)-7-(1-oxophosphoran-1-yl) -1H -indole-6-carbonitrile, Example 8 (18 mg, 0.038 mmol, 29% yield).

製備型HPLC純化條件：管柱/尺寸：YMC C18(19*250*5µm)；流動相A：10mM ABC於水中；移動相B：乙腈梯度（時間/%B）：0.01/15、1/15、10 /45、14.5/45、14.6/100、18/100、18.1/15、21/15。流速：18mL/min。溶解度：THF+ACN。Preparative HPLC purification conditions: column/size: YMC C18 (19*250*5µm); mobile phase A: 10mM ABC in water; mobile phase B: acetonitrile gradient (time/%B): 0.01/15, 1/15 , 10/45, 14.5/45, 14.6/100, 18/100, 18.1/15, 21/15. Flow rate: 18mL/min. Solubility: THF+ACN.

MS-(LCMS) m/z：C 23H 26ClN 6OP [M-H] -之計算值= 467.16，觀察值= 467.38。LCMS純度：98.87%；HPLC純度：97.05%； 1H NMR (400 MHz, DMSO- d 6 ) (D 2O交換-VT at 90℃) δ 8.88 (dd, J= 1.6, 8.4 Hz, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J= 3.2, 8.4 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.34 – 3.16 (m, 1H), 2.61 – 2.52 (m, 1H), 2.44 – 2.34 (m, 3H), 2.30 – 2.21 (m, 6H), 2.10 – 2.03 (m, 1H), 1.75 – 1.66 (m, 1H), 1.48 – 1.37 (m, 1H), 1.26 – 1.16 (m, 1H), 1.04 (d, J= 6.4 Hz, 3H)。 實例13 3-(5-甲基-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 MS- ( LCMS) m/z : Calcd. for C23H26ClN6OP [MH] - = 467.16 , observed = 467.38. LCMS purity: 98.87%; HPLC purity: 97.05%; 1 H NMR (400 MHz, DMSO- d 6 ) (D 2 O exchange-VT at 90°C) δ 8.88 (dd, J = 1.6, 8.4 Hz, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J = 3.2, 8.4 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.34 – 3.16 (m, 1H), 2.61 – 2.52 ( m, 1H), 2.44 – 2.34 (m, 3H), 2.30 – 2.21 (m, 6H), 2.10 – 2.03 (m, 1H), 1.75 – 1.66 (m, 1H), 1.48 – 1.37 (m, 1H), 1.26 – 1.16 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). Example 13 3-(5-methyl-2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxo Phosphane-1-yl)-1 H -indole-6-carbonitrile

在微波小瓶中，在室溫下向 中間物 9（二批，2 × 40mg，2 × 0.066mmol）於1,4-二 烷/H 2O (1.0mL)中之經氬除氣溶液添加甲基硼酸(2 x 40mg, 2 x 0.33mmol)、Cs 2CO 3(2 x 65mg, 2 x 0.20mmol)、Catacxium (2 x 24mg, 2 x 0.066mmol)、及Pd(OAc) 2(2 x 7.4mg, 2 x 0.033mmol)。在微波反應器中於100℃下攪拌反應混合物2h。在起始材料消耗後，將反應混合物用乙酸乙酯(10mL)稀釋，經由矽藻土墊過濾，將濾液在減壓下濃縮，以得到粗化合物。將粗化合物藉由矽膠管柱層析法使用2至3%於DCM中之甲醇來純化，以給出苄基(2S,5S)-5-((4-(6-氰基-7-(1-氧代磷烷-1-基)-1 H-吲哚-3-基)-5-甲基嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（60mg，0.10mmol，78%產率）。MS-(LCMS) m/z：C 32H 35N 6O 3P [M+H] +之計算值= 583.25，觀察值= 583.55。LCMS純度：88.50%。 In a microwave vial, intermediate 9 (two batches, 2 × 40 mg, 2 × 0.066 mmol) in 1,4-di To an argon-degassed solution in alkane/H 2 O (1.0 mL) was added methylboronic acid (2 x 40 mg, 2 x 0.33 mmol), Cs 2 CO 3 (2 x 65 mg, 2 x 0.20 mmol), Catacxium (2 x 24mg, 2 x 0.066mmol), and Pd(OAc) 2 (2 x 7.4mg, 2 x 0.033mmol). The reaction mixture was stirred at 100 °C for 2 h in a microwave reactor. After the starting material was consumed, the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography using 2 to 3% methanol in DCM to give benzyl (2S,5S)-5-((4-(6-cyano-7-( 1-oxophosphorane-1-yl) -1H -indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate ( 60 mg, 0.10 mmol, 78% yield). MS- ( LCMS) m/z : Calcd . for C32H35N6O3P [M+H] + = 583.25 , observed = 583.55. LCMS purity: 88.50%.

在室溫下向苄基(2S,5S)-5-((4-(6-氰基-7-(1-氧代磷烷-1-基)-1 H-吲哚-3-基)-5-甲基嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（二批，2 × 30mg，2 × 0.051mmol）於DCM (0.4mL)中之攪拌溶液添加Et 3N (2 x 2.9µL, 2 x 0.021mmol)、Et 3SiH (2 x 41µL, 2 x 30mg, 2 x 0.26mmol)、及Pd(OAc) 2(2 x 2.3mg, 2 x 0.010mmol)。將反應混合物在45℃下攪拌1.5h。藉由TLC消耗起始材料後，將反應混合物在減壓下濃縮。將粗化合物藉由製備型HPLC純化，以給出3-(5-甲基-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈， 實例 13（7.0mg，0.015mmol，15%產率）。 Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxophosphoran-1-yl)-1 H -indol-3-yl) - A stirred solution of 5-methylpyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate (two batches, 2×30 mg, 2×0.051 mmol) in DCM (0.4 mL) Add Et 3 N (2 x 2.9µL, 2 x 0.021mmol), Et 3 SiH (2 x 41µL, 2 x 30mg, 2 x 0.26mmol), and Pd(OAc) 2 (2 x 2.3mg, 2 x 0.010mmol ). The reaction mixture was stirred at 45 °C for 1.5 h. After consumption of starting material by TLC, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 3-(5-methyl-2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)pyrimidine-4 -yl)-7-(1-oxophosphoran-1-yl) -1H -indole-6-carbonitrile, Example 13 (7.0 mg, 0.015 mmol, 15% yield).

MS-(LCMS) m/z：C 24H 29N 6OP [M+H] +之計算值= 449.21，觀察值= 449.57。LCMS純度：97.42%；HPLC純度：98.66%；對掌性纯度：98.84； 1H NMR (400 MHz, DMSO- d 6 ) δ 11.85 (br s, 1H, NH), 8.91 (d, J= 8.0 Hz, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.53 (d, J= 8.0 Hz, 1H), 6.53 (br s, 1H, NH), 3.81 – 3.69 (m, 1H), 3.20 – 3.11 (m, 1H), 2.50 – 2.30 (m, 4H), 2.28 (s, 3H), 2.30 – 1.96 (m, 7H), 1.70 – 1.60 (m, 1H), 1.43 – 1.30 (m, 1H), 1.19 – 1.06 (m, 1H), 1.04 (d, J= 6.2 Hz, 3H)。 MS- ( LCMS) m/z : calcd for C24H29N6OP [M+H] + = 449.21 , observed = 449.57. LCMS purity: 97.42%; HPLC purity: 98.66%; chiral purity: 98.84; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.85 (br s, 1H, NH), 8.91 (d, J = 8.0 Hz , 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.53 (br s, 1H, NH), 3.81 – 3.69 (m, 1H), 3.20 – 3.11 (m, 1H), 2.50 – 2.30 (m, 4H), 2.28 (s, 3H), 2.30 – 1.96 (m, 7H), 1.70 – 1.60 (m, 1H), 1.43 – 1.30 (m, 1H) , 1.19 – 1.06 (m, 1H), 1.04 (d, J = 6.2 Hz, 3H).

於 表 3中之實例係使用與針對 實例 8 及 13之合成所述相似之方法來製備。 表 3 實例編號 結構 名稱 質量離子計算值 / 觀測值 9 ( S)-3-(5-氯-2-((5,5-二甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 483.18/483.30 10 ( S)-3-(5-氯-2-((6,6-二甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 481.18/481.36 (neg) 11 ( S)-3-(5-氯-2-(哌啶-3-基胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 455.14/455.10 12 3-(5-氯-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷 -1-基)-1 H-吲哚-6-甲腈 483.18/483.20 14 ( S)-3-(2-((5,5-二甲基哌啶-3-基)胺基)-5-甲基嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 463.23/463.82 15 ( S)-3-(5-甲基-2-(哌啶-3-基胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 435.20/435.21 16 3-(5-甲基-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷 -1-基)-1 H-吲哚-6-甲腈 463.23/463.82 17 ( S)-3-(2-((6,6-二甲基哌啶-3-基)胺基)-5-甲基嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈 463.54/463.50 實例 18 N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-羧醯胺（圖6） The examples in Table 3 were prepared using methods similar to those described for the synthesis of Examples 8 and 13 . Table 3 instance number structure name Mass ion calculated value / observed value 9 ( S )-3-(5-chloro-2-((5,5-dimethylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxophosphorane-1 -yl)-1 H -indole-6-carbonitrile 483.18/483.30 10 ( S )-3-(5-chloro-2-((6,6-dimethylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxophosphorane-1 -yl)-1 H -indole-6-carbonitrile 481.18/481.36 (neg) 11 ( S )-3-(5-Chloro-2-(piperidin-3-ylamino)pyrimidin-4-yl)-7-(1-oxophosphorane-1-yl)-1 H -indole -6-carbonitrile 455.14/455.10 12 3-(5-chloro-2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxophosphorus -1-yl)-1 H -indole-6-carbonitrile 483.18/483.20 14 ( S )-3-(2-((5,5-dimethylpiperidin-3-yl)amino)-5-methylpyrimidin-4-yl)-7-(1-oxophosphorane- 1-yl)-1 H -indole-6-carbonitrile 463.23/463.82 15 ( S )-3-(5-methyl-2-(piperidin-3-ylamino)pyrimidin-4-yl)-7-(1-oxophosphorane-1-yl)-1 H -ind Indole-6-carbonitrile 435.20/435.21 16 3-(5-Methyl-2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxophosphorus -1-yl)-1 H -indole-6-carbonitrile 463.23/463.82 17 ( S )-3-(2-((6,6-Dimethylpiperidin-3-yl)amino)-5-methylpyrimidin-4-yl)-7-(1-oxophosphorane- 1-yl)-1 H -indole-6-carbonitrile 463.54/463.50 Example 18 N- (3,5-Dimethyliso Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl )-1 H -pyrrolo[2,3- b ]pyridine-6-carboxamide (Figure 6)

在0℃下向 中間物 4（800mg，粗產物）於DMF (10mL)中之攪拌溶液添加DIPEA (2.21mL, 12.7mmol)、HOBt (512mg, 3.79mmol)、及EDC-HCl (720mg, 3.76mmol)。將反應混合物攪拌10min，然後在室溫下添加3,5-二甲基異 唑-4-胺(420mg, 3.75mmol)。將反應混合物在室溫下攪拌16h。在藉由TLC消耗起始材料後，將反應混合物用冰水(20mL)淬滅，並用乙酸乙酯(2 x 100mL)萃取。將合併之有機層用Na2SO4乾燥並蒸發，以得到粗化合物。粗化合物藉由矽膠(100-200)管柱層析法使用70至80%於石油醚（作為洗提液）中之EtOAc來純化，以給出 N-(3,5-二甲基異 唑-4-基)-3-(2-(甲基硫基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3 - b]吡啶-6-羧醯胺（300mg，0.669mmol，35%經過2個步驟）。MS-(LCMS) m/z：C 19H 15F 3N 6O 2S [M+H] +之計算值= 449.09，觀察值= 449.24。 1H NMR (400 MHz, DMSO- d 6 ) δ 12.72 (br s, 1H, NH), 9.98 (s, 1H), 8.99 (s, 1H), 8.77 (d, J= 8.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J= 8.0 Hz, 1H), 2.67 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H)。 To a stirred solution of Intermediate 4 (800 mg, crude product) in DMF (10 mL) at 0 °C was added DIPEA (2.21 mL, 12.7 mmol), HOBt (512 mg, 3.79 mmol), and EDC-HCl (720 mg, 3.76 mmol) ). The reaction mixture was stirred for 10 min, then 3,5-dimethyliso Azol-4-amine (420mg, 3.75mmol). The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated to give crude compound. The crude compound was purified by column chromatography on silica gel (100-200) using 70 to 80% EtOAc in petroleum ether (as eluent) to give N- (3,5-dimethyliso Azol-4-yl)-3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-6- Carboxamide (300 mg, 0.669 mmol, 35% over 2 steps). MS-(LCMS) m/z : calcd for C19H15F3N6O2S [ M +H] + = 449.09 , observed = 449.24 . 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.72 (br s, 1H, NH), 9.98 (s, 1H), 8.99 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H).

在-40℃下向 N-(3,5-二甲基異 唑-4-基)-3-(2-(甲基硫基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-羧醯胺(300mg, 0.669mmol)於1,2-DME (8mL)中之攪拌溶液，添加 m-CPBA (~70%, 412mg, 1.67mmol)，並在-40℃下攪拌2h。在反應完成後，將反應混合物用水(10mL)淬滅，並用乙酸乙酯(2 x 20mL)萃取。將合併之有機層用Na 2SO 4乾燥並蒸發，以給出 N-(3,5-二甲基異 唑-4-基)-3-(2-(甲基磺醯基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-羧醯胺（400mg，粗產物未經純化即用於下一步驟）。MS-(LCMS) m/z：C 19H 15F 3N 6O 4S [M+H] +之計算值= 481.08，觀察值= 481.26。 N- (3,5-dimethyl iso Azol-4-yl)-3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-6- A stirred solution of carboxamide (300mg, 0.669mmol) in 1,2-DME (8mL) was added with m -CPBA (~70%, 412mg, 1.67mmol) and stirred at -40°C for 2h. After completion of the reaction, the reaction mixture was quenched with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na2SO4 and evaporated to give N- (3,5 - dimethyliso Azol-4-yl)-3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-6 -Carboxamide (400 mg, the crude product was used in the next step without purification). MS-(LCMS) m/z : Calcd . for C19H15F3N6O4S [M+H] + = 481.08 , observed = 481.26.

向 N-(3,5-二甲基異 唑-4-基)-3-(2-(甲基磺醯基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-羧醯胺（400mg，粗產物）於THF (5mL)中之攪拌溶液添加DIPEA (0.76mL, 4.4mmol)、苄基(2 S,5 S)-5-胺基-2-甲基哌啶-1-羧酸酯HCl鹽(191mg, 0.669mmol)，並在室溫下攪拌1h。在藉由TLC消耗起始材料後，將反應混合物用水(10mL)淬滅，用乙酸乙酯(2 x 50mL)萃取。將有機層分離，用Na 2SO 4乾燥，過濾並蒸發。將粗產物藉由矽膠(100-200)管柱層析法使用40至50%於石油醚中之EtOAc來純化，以給出苄基(2 S,5 S)-5-((4-(6-((3,5-二甲基異 唑-4-基)胺甲醯基)-1 H-吡咯并[2,3- b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（60mg，0.092mmol，14%產率經過兩個步驟）。MS-(LCMS) m/z：C 32H 31F 3N 8O 4[M+H] +之計算值= 649.24，觀察值= 649.57。 to N- (3,5-dimethyliso Azol-4-yl)-3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-6 - To a stirred solution of carboxamide (400 mg, crude product) in THF (5 mL) was added DIPEA (0.76 mL, 4.4 mmol), benzyl (2 S ,5 S )-5-amino-2-methylpiperidine -1-carboxylate HCl salt (191 mg, 0.669 mmol), and stirred at room temperature for 1 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 50 mL). The organic layer was separated, dried over Na2SO4 , filtered and evaporated. The crude product was purified by column chromatography on silica gel (100-200) using 40 to 50% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((4-( 6-((3,5-Dimethyliso Azol-4-yl)carbamoyl) -1H -pyrrolo[2,3- b ]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2 -Methylpiperidine-1-carboxylate (60 mg, 0.092 mmol, 14% yield over two steps). MS-(LCMS) m/z : Calcd. for C32H31F3N8O4 [M+H] + = 649.24, observed = 649.57.

在0℃下向苄基(2 S,5 S)-5-((4-(6-((3,5-二甲基異 唑-4-基)胺甲醯基)-1 H-吡咯并[2,3- b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯(60mg, 0.092mmol)於DCM (1mL)中之攪拌溶液添加BBr 3（1M在DCM中）(0.5mL)，並在0℃下攪拌30min。將反應混合物用冰水(1mL)淬滅並蒸發。藉由製備型HPLC純化粗產物，以給出 N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3-b]吡啶-6-羧醯胺， 實例 18（7.0mg，0.014mmol，15%產率）。 Benzyl (2 S ,5 S )-5-((4-(6-((3,5-dimethyliso Azol-4-yl)carbamoyl) -1H -pyrrolo[2,3- b ]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2 - A stirred solution of methylpiperidine-1-carboxylate (60 mg, 0.092 mmol) in DCM (1 mL) was added BBr 3 (1 M in DCM) (0.5 mL) and stirred at 0° C. for 30 min. The reaction mixture was quenched with ice water (1 mL) and evaporated. The crude product was purified by preparative HPLC to give N- (3,5-dimethyliso Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -pyrrolo[2,3-b]pyridine-6-carboxamide, Example 18 (7.0 mg, 0.014 mmol, 15% yield).

製備型HPLC方法：管柱/尺寸：X橋苯基(19*250*5um)；移動相A：10 MM ABC於水(aq)中；移動相B：乙腈(org)；梯度（時間/%B）：0 /25、1/25、09/55、11.8./55、11.9/100、14.8/100、14.9/25、17/25。流速：19mL/min；溶解度：乙腈+THF+水。Preparative HPLC method: column/size: X-bridged phenyl group (19*250*5um); mobile phase A: 10 MM ABC in water (aq); mobile phase B: acetonitrile (org); gradient (time/% B): 0/25, 1/25, 09/55, 11.8./55, 11.9/100, 14.8/100, 14.9/25, 17/25. Flow rate: 19mL/min; solubility: acetonitrile+THF+water.

MS-(LCMS) m/z：C 24H 25F 3N 8O 2[M-H] -之計算值= 513.21，觀察值= 513.32。 1H NMR (400 MHz, DMSO- d 6 ) VT at 90℃δ 12.72 (br s, 1H, NH), 9.61 (s, 1H, NH), 8.81 (d, J= 8.4 Hz, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H, NH), 3.92 – 3.83 (m, 1H), 3.22 – 3.15 (m, 1H), 2.60 – 2.47 (m, 2H), 2.33 (s, 3H), 2.16 (s, 3H), 2.07 – 2.00 (m, 1H), 1.72 – 1.64 (m, 1H), 1.55 – 1.41 (m, 1H), 1.20 – 1.10 (m, 1H), 1.00 (d, J= 6.0 Hz, 3H)。LCMS純度：98.68%，UPLC純度：97.62%。 MS-(LCMS) m/z : Calcd. for C24H25F3N8O2 [MH ] - = 513.21 , observed = 513.32. 1 H NMR (400 MHz, DMSO- d 6 ) VT at 90℃δ 12.72 (br s, 1H, NH), 9.61 (s, 1H, NH), 8.81 (d, J = 8.4 Hz, 1H), 8.55 ( s, 1H), 8.07 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H, NH), 3.92 – 3.83 (m, 1H), 3.22 – 3.15 (m, 1H), 2.60 – 2.47 (m, 2H), 2.33 (s, 3H), 2.16 (s, 3H), 2.07 – 2.00 (m, 1H), 1.72 – 1.64 (m, 1H), 1.55 – 1.41 (m, 1H), 1.20 – 1.10 (m, 1H), 1.00 (d, J = 6.0 Hz, 3H). LCMS purity: 98.68%, UPLC purity: 97.62%.

於 表 4中之實例係使用與針對 實例 18之合成所述相似之方法來製備。 表 4 實例編號 結構 名稱 質量離子計算值 / 觀測值 19 (3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-基)(嗎啉基)甲酮 490.21/490.26 20 (3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-基)(哌 -1-基)甲酮 487.23/487.46 (neg) 21 (4-甲基哌 -1-基)(3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-基)甲酮 501.24/501.48 (neg) 22 (3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-基)(哌啶-1-基)甲酮 486.23/486.36 (neg) 23 (3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-基)(吡咯啶-1-基)甲酮 474.22/474.52 24 吖呾-1-基(3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3-b ]吡啶-6-基)甲酮 460.20/460.50 25 N,N-二乙基-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3-b]吡啶-6-羧醯胺 476.23/476.59 26 N,N-二甲基-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3-b]吡啶-6-羧醯胺 446.20/446.40 (neg) 27 N-乙基- N-異丙基-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-羧醯胺 488.25/488.40 (neg) 實例 28N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-羧醯胺（圖7） The examples in Table 4 were prepared using methods similar to those described for the synthesis of Example 18 . Table 4 instance number structure name Mass ion calculated value / observed value 19 (3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrole And[2,3- b ]pyridin-6-yl)(morpholinyl)methanone 490.21/490.26 20 (3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrole And[2,3- b ]pyridin-6-yl)(piper -1-yl)methanone 487.23/487.46 (neg) twenty one (4-Methylpiperene -1-yl)(3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) -1 H -pyrrolo[2,3- b ]pyridin-6-yl)methanone 501.24/501.48 (neg) twenty two (3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrole And[2,3- b ]pyridin-6-yl)(piperidin-1-yl)methanone 486.23/486.36 (neg) twenty three (3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -pyrrole And[2,3- b ]pyridin-6-yl)(pyrrolidin-1-yl)methanone 474.22/474.52 twenty four Aziridine-1-yl(3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -pyrrolo[2,3-b]pyridin-6-yl)methanone 460.20/460.50 25 N,N -Diethyl-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4- base)-1 H -pyrrolo[2,3-b]pyridine-6-carboxamide 476.23/476.59 26 N,N -Dimethyl-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4- base)-1 H -pyrrolo[2,3-b]pyridine-6-carboxamide 446.20/446.40 (neg) 27 N -Ethyl- N -isopropyl-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine -4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide 488.25/488.40 (neg) Example 28 N-(3,5-Dimethyliso Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -indole-6-carboxamide (Figure 7)

向1 H-吲哚-6-羧酸（二批，2 × 5.00g，2 × 31.0mmol）於DMF (60mL)中之攪拌溶液添加DIPEA (2 x 16.2mL, 93.0mmol)、及HATU (2 x 14.1g, 37.2mmol)。將反應混合物攪拌10min，接著添加3,5-二甲基異 唑-4-胺(2 x 3.48g, 31.0mmol)。在室溫下將反應混合物攪拌16h。在藉由TLC消耗初始材料後，將反應混合物用冰水(250mL)淬滅，並用乙酸乙酯(2 x 100mL)萃取，蒸發溶劑以得到粗化合物。將合併之粗化合物藉由矽膠(100-200)管柱層析法使用70至80%於石油醚中之EtOAc來純化，以給出 N-(3,5-二甲基異 唑-4-基)-1 H-吲哚-6-羧醯胺（10.0g，39.2mmol，63%產率）。MS-(LCMS) m/z：C 14H 13N 3O 2[M+H] +之計算值= 256.10，觀察值= 256.22。 To a stirred solution of 1H -indole-6-carboxylic acid (two batches, 2 x 5.00 g, 2 x 31.0 mmol) in DMF (60 mL) was added DIPEA (2 x 16.2 mL, 93.0 mmol), and HATU (2 x 14.1 g, 37.2 mmol). The reaction mixture was stirred for 10 min, followed by the addition of 3,5-dimethyliso Azol-4-amine (2 x 3.48 g, 31.0 mmol). The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material by TLC, the reaction mixture was quenched with ice water (250 mL) and extracted with ethyl acetate (2 x 100 mL), the solvent was evaporated to give the crude compound. The combined crude compounds were purified by column chromatography on silica gel (100-200) using 70 to 80% EtOAc in petroleum ether to give N- (3,5-dimethyliso Azol-4-yl) -1H -indole-6-carboxamide (10.0 g, 39.2 mmol, 63% yield). MS-(LCMS) m/z : Calcd . for C14H13N3O2 [M+H] + = 256.10 , observed = 256.22.

在密封管中，在室溫下向2,4-二氯-5-(三氟甲基)嘧啶(15.176g, 69.95mmol)於DCE (60mL)中之攪拌溶液添加AlCl 3(4.694g, 35.21mmol)，並在80℃下攪拌30min。隨後於80℃下添加 N-(3,5-二甲基異 唑-4-基)-1 H-吲哚-6-羧醯胺(6.000g, 23.50mmol)至上述反應混合物，並攪拌16h。在藉由TLC反應完成後，將反應混合物用冰冷之水(60mL)淬滅，用10%於乙酸乙酯中之THF(2 x 300mL)萃取。將合併之有機層用鹽水(150mL)洗滌，用Na 2SO 4乾燥，過濾並蒸發，以得到半純的化合物。將粗化合物藉由矽膠管柱層析法使用30%於石油醚中之EtOAc來純化，以給出部分純的3-(2-氯-5-(三氟甲基)嘧啶-4-基)- N-(3,5-二甲基異 唑-4-基)-1 H-吲哚-6-羧醯胺，其藉由製備型HPLC純化，以給出純的所欲產物（700mg，1.61mmol，7%產率）。藉由 19F HOESY進一步確認結構。MS-(LCMS) m/z：C 19H 13ClF 3N 5O 2[M+H] +之計算值= 436.06，觀察值= 436.34。 1H NMR (400 MHz, DMSO-d 6) δ 12.56 (s, 1H), 9.83 (s, 1H), 9.08 (s, 1H), 8.43 (d, J= 8.80 Hz, 1H)), 8.25 (s, 1H)), 8.20 (s, 1H), 7.88 (d, J= 8.80 Hz, 1H)), 2.34 (s, 3H), 2.16 (s, 3H)。 To a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (15.176 g, 69.95 mmol) in DCE (60 mL) was added AlCl 3 (4.694 g, 35.21 mmol), and stirred at 80°C for 30min. Then add N- (3,5-dimethyliso Azol-4-yl) -1H -indole-6-carboxamide (6.000g, 23.50mmol) was added to the above reaction mixture and stirred for 16h. After completion of the reaction by TLC, the reaction mixture was quenched with ice-cold water (60 mL), extracted with 10% THF in ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4 , filtered and evaporated to give semi-pure compound. The crude compound was purified by silica gel column chromatography using 30% EtOAc in petroleum ether to give partially pure 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl) - N -(3,5-Dimethyliso (Azol-4-yl) -1H -indole-6-carboxamide, which was purified by preparative HPLC to give pure desired product (700 mg, 1.61 mmol, 7% yield). The structure was further confirmed by 19 F HOESY. MS-(LCMS) m/z : Calcd . for C19H13ClF3N5O2 [M+H] + = 436.06 , observed = 436.34. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.56 (s, 1H), 9.83 (s, 1H), 9.08 (s, 1H), 8.43 (d, J = 8.80 Hz, 1H)), 8.25 (s , 1H)), 8.20 (s, 1H), 7.88 (d, J = 8.80 Hz, 1H)), 2.34 (s, 3H), 2.16 (s, 3H).

製備型HPLC方法：管柱/尺寸：X-橋-C18 (19*250*5um)；移動相A：水中之10mM碳酸氫銨；流動相B：CAN；梯度（時間/%B）：0/35、3/35、15/75、18/75、18.1/100、20/100、20.1/35、22/35；流速：17mL/min。溶解度：水+THF+ACN。Preparative HPLC method: column/size: X-bridge-C18 (19*250*5um); mobile phase A: 10mM ammonium bicarbonate in water; mobile phase B: CAN; gradient (time/%B): 0/ 35, 3/35, 15/75, 18/75, 18.1/100, 20/100, 20.1/35, 22/35; flow rate: 17mL/min. Solubility: water+THF+ACN.

向3-(2-氯-5-(三氟甲基)嘧啶-4-基)- N-(3,5-二甲基異 唑-4-基)-1 H-吲哚-6-羧醯胺(700mg, 1.61mmol)於NMP (10mL)中之攪拌溶液添加DIPEA (1.40mL, 8.05mmol)、苄基(2 S,5 S)-5-胺基-2-甲基哌啶-1-羧酸酯鹽酸鹽(458mg, 1.61mmol)，並在120℃下攪拌16h。在起始材料消耗後，將反應混合物用水(50mL)淬滅，用乙酸乙酯(2 x 100mL)萃取。分離合併之有機層，用Na 2SO 4乾燥，過濾並蒸發。將粗產物藉由矽膠(100-200)管柱層析法使用20至30%於石油醚中之EtOAc來純化，以給出苄基(2 S,5 S)-5-((4-(6-((3,5-二甲基異 唑-4-基)胺甲醯基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯（500mg，0.772mmol，48%產率）。MS-(LCMS) m/z：C 33H 32F 3N 7O 4[M+H] +之計算值= 648.25，觀察值= 648.54。 To 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl) -N- (3,5-dimethyliso To a stirred solution of azol-4-yl) -1H -indole-6-carboxamide (700mg, 1.61mmol) in NMP (10mL) was added DIPEA (1.40mL, 8.05mmol), benzyl ( 2S ,5 S )-5-Amino-2-methylpiperidine-1-carboxylate hydrochloride (458mg, 1.61mmol), and stirred at 120°C for 16h. After the starting material was consumed, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layers were separated, dried over Na2SO4 , filtered and evaporated. The crude product was purified by silica gel (100-200) column chromatography using 20 to 30% EtOAc in petroleum ether to give benzyl ( 2S , 5S )-5-((4-( 6-((3,5-Dimethyliso Azol-4-yl)carbamoyl) -1H -indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidin-1- Carboxylate (500 mg, 0.772 mmol, 48% yield). MS-(LCMS) m/z : Calcd. for C33H32F3N7O4 [M+H] + = 648.25 , observed = 648.54.

向苄基(2 S,5 S)-5-((4-(6-((3,5-二甲基異 唑-4-基)胺甲醯基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)-2-甲基哌啶-1-羧酸酯(500mg, 0.772mmol)於DCM (5mL)中之攪拌溶液添加BBr 3(1M於DCM, 3.9mL, 3.9mmol)，並在室溫下攪拌3h。在藉由TLC消耗起始材料後，將反應混合物用水(50mL)淬滅，用乙酸乙酯(2 x 100mL)萃取。將合併之有機層分離，用Na 2SO 4乾燥，過濾且蒸發，以得到粗材料，其藉由製備型HPLC純化以給出 N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-羧醯胺， 實例 28(200mg, 0.389mmol, 50%)。 To benzyl (2 S ,5 S )-5-((4-(6-((3,5-dimethyliso Azol-4-yl)carbamoyl) -1H -indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidin-1- A stirred solution of the carboxylate (500 mg, 0.772 mmol) in DCM (5 mL) was added BBr3 (IM in DCM, 3.9 mL, 3.9 mmol) and stirred at room temperature for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layers were separated, dried over Na 2 SO 4 , filtered and evaporated to give crude material which was purified by preparative HPLC to give N- (3,5-dimethyliso Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -indole-6-carboxamide, Example 28 (200mg, 0.389mmol, 50%).

製備型HPLC方法：管柱/尺寸：X-橋苯基((19*250*5µm)；流動相A：於水中10mM ABC；流動相B：乙腈；梯度（時間/%B）：0.01/20、1/20、10/40、17/40、17.1/100、21/100、21.1/20、23/20；流速：18mL/min；溶解度：乙腈+THF+水。Preparative HPLC method: column/size: X-endophenyl ((19*250*5µm); mobile phase A: 10mM ABC in water; mobile phase B: acetonitrile; gradient (time/%B): 0.01/20 , 1/20, 10/40, 17/40, 17.1/100, 21/100, 21.1/20, 23/20; flow rate: 18mL/min; solubility: acetonitrile + THF + water.

MS-(LCMS) m/z：C 25H 26F 3N 7O 2[M+H] +之計算值= 514.21，觀察值= 514.29。 1H NMR (400 MHz, DMSO- d 6 ) VT於90℃下；δ 11.81 (br s, 1H, NH), 9.47 (s, 1H, NH), 8.53 (s, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.74 (d, J= 8.40 Hz, 1H), 7.34 (d, J= 8.00 Hz, 1H, NH), 3.96 – 3.83 (m, 1H), 3.21 – 3.15 (m, 1H), 2.60 – 2.48 (m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.10 – 2.00 (m, 1H), 1.72 – 1.66 (m, 1H), 1.52 – 1.42 (m, 1H), 1.20 – 1.07 (m, 1H), 1.00 (d, J= 6.00 Hz, 3H)。LC-MS純度：97.11%；HPLC純度：98.63%。 MS- ( LCMS) m/z : Calcd. for C25H26F3N7O2 [M+H] + = 514.21 , observed = 514.29. 1 H NMR (400 MHz, DMSO- d 6 ) VT at 90°C; δ 11.81 (br s, 1H, NH), 9.47 (s, 1H, NH), 8.53 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H, NH), 3.96 – 3.83 (m, 1H), 3.21 – 3.15 (m, 1H), 2.60 – 2.48 (m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.10 – 2.00 (m, 1H), 1.72 – 1.66 (m, 1H), 1.52 – 1.42 (m, 1H), 1.20 – 1.07 (m, 1H), 1.00 (d, J = 6.00 Hz, 3H). LC-MS purity: 97.11%; HPLC purity: 98.63%.

於 表 5中之實例係使用與針對 實例 28之合成所述相似之方法來製備。 表 5 實例編號 結構 名稱 質量離子計算值 / 觀測值 29 第一步驟反應起始材料係7-溴-1 H-吲哚-6-羧酸。7-二甲基磷醯基以與上述實例相似之方式取代溴。 N-(3,5-二甲基異 唑-4-基)-7-(二甲基磷醯基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-羧醯胺 590.22/590.44 30 (3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-基)(嗎啉基)甲酮 489.21/489.36 31 第一步驟反應起始材料係7-氟基-1 H-吲哚-6-羧酸。（參考文獻： Eur. J. Org. Chem. 2006, 2956-2969） (7-氟-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-基)(嗎啉基)甲酮 505.21/505.51 (neg) 實例 32( S)-7-(1,1-二氧代異四氫噻唑-2-基)-3-(2-(哌啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 The examples in Table 5 were prepared using methods similar to those described for the synthesis of Example 28 . Table 5 instance number structure name Mass ion calculated value / observed value 29 The starting material for the first step reaction is 7-bromo-1 H -indole-6-carboxylic acid. 7-Dimethylphosphoryl is substituted for bromine in a similar manner to the above example. N -(3,5-Dimethyliso Azol-4-yl)-7-(dimethylphosphoryl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carboxamide 590.22/590.44 30 (3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -ind Indol-6-yl)(morpholinyl)methanone 489.21/489.36 31 The starting material for the first step reaction is 7-fluoro-1 H -indole-6-carboxylic acid. (Reference: Eur. J. Org. Chem. 2006 , 2956-2969) (7-fluoro-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1 H -indol-6-yl)(morpholinyl)methanone 505.21/505.51 (neg) Example 32 ( S )-7-(1,1-dioxoisotetrahydrothiazol-2-yl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) Pyrimidin-4-yl) -1H -indole-6-carbonitrile

向 中間物 5(120mg, 0.272mmol)於NMP (1.21mL)中之攪拌溶液添加DIPEA (237µL, 1.36mmol)、第三-丁基(S)-3-胺基哌啶-1-羧酸酯(54.4mg, 0.272mmol)，並在140℃下攪拌16h。在起始材料消耗後，將反應混合物用水(10mL)淬滅，用乙酸乙酯(2 x 15mL)萃取。分離合併之有機層，用Na 2SO 4乾燥，過濾並蒸發。將粗產物藉由矽膠(100-200)管柱層析法使用50至70%於石油醚中之EtOAc來純化，以給出第三-丁基( S)-3-((4-(6-氰基-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-羧酸酯（113mg，0.186mmol，69%產率）。MS-(LC-MS) m/z：C 27H 30F 7N 7O 4S [M+H] +之計算值= 606.20，觀察值= 606.58。 To a stirred solution of Intermediate 5 (120 mg, 0.272 mmol) in NMP (1.21 mL) was added DIPEA (237 µL, 1.36 mmol), tert-butyl(S)-3-aminopiperidine-1-carboxylate (54.4mg, 0.272mmol), and stirred at 140°C for 16h. After the starting material was consumed, the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 15 mL). The combined organic layers were separated, dried over Na2SO4 , filtered and evaporated. The crude product was purified by column chromatography on silica gel (100-200) using 50 to 70% EtOAc in petroleum ether to give tert-butyl( S )-3-((4-(6 -Cyano-7-(1,1-dioxoisotetrahydrothiazol-2-yl) -1H -indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amine yl) piperidine-1-carboxylate (113 mg, 0.186 mmol, 69% yield). MS-(LC-MS) m/z : Calcd . for C27H30F7N7O4S [ M +H] + = 606.20, observed = 606.58.

在0℃下向第三-丁基( S)-3-((4-(6-氰基-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)胺基)哌啶-1-羧酸酯(120mg, 0.198mmol)於DCM (3mL)中之攪拌溶液添加TFA (76µL, 0.99mmol)，並在0℃下攪拌30min。在藉由TLC消耗起始材料後，將反應混合物在真空下濃縮。將所得之粗材料藉由combi-flash (C-18)使用0.1% ABC緩衝液來純化，以給出( S)-7-(1,1-二氧代異四氫噻唑-2-基)-3-(2-(哌啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈， 實例 32（22mg，0.044mmol，22%產率）。 3-Butyl( S )-3-((4-(6-cyano-7-(1,1-dioxoisotetrahydrothiazol-2-yl)-1 H -ind A stirred solution of indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (120 mg, 0.198 mmol) in DCM (3 mL) was added TFA ( 76µL, 0.99mmol), and stirred at 0°C for 30min. After consumption of starting material by TLC, the reaction mixture was concentrated under vacuum. The resulting crude material was purified by combi-flash (C-18) using 0.1% ABC buffer to give ( S )-7-(1,1-dioxoisotetrahydrothiazol-2-yl) -3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl) -1H -indole-6-carbonitrile, Example 32 (22mg, 0.044mmol , 22% yield).

MS-(LCMS) m/z：C 22H 22F 3N 7O 2S [M-H] -之計算值= 504.15，觀察值= 504.25。LCMS純度：98.78%；UPLC純度：98.60%； 1H NMR (400 MHz, DMSO- d 6 , D 2O交換-VT at 90℃) δ 8.58 (s, 1H), 8.35 (d, J= 8.1 Hz, 1H), 8.03 (s, 1H), 7.56 (d, J= 8.1 Hz, 1H), 3.95 (d, J= 6.6 Hz, 2H), 3.98 – 3.89 (m, 1H), 3.56 (d, J= 7.4 Hz, 2H), 3.10 (dd, J= 3.2, 12.0 Hz, 1H), 2.86 – 2.77 (m, 1H), 2.74 – 2.63 (m, 2H), 2.60 – 2.50 (m, 2H), 2.02 – 1.94 (m, 1H), 1.74 – 1.64 (m, 1H), 1.62 – 1.42 (m, 2H)。 MS- (LCMS ) m/z : Calcd. for C22H22F3N7O2S [MH] - = 504.15, observed = 504.25 . LCMS purity: 98.78%; UPLC purity: 98.60%; 1 H NMR (400 MHz, DMSO- d 6 , D 2 O exchange-VT at 90℃) δ 8.58 (s, 1H), 8.35 (d, J = 8.1 Hz , 1H), 8.03 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 3.95 (d, J = 6.6 Hz, 2H), 3.98 – 3.89 (m, 1H), 3.56 (d, J = 7.4 Hz, 2H), 3.10 (dd, J = 3.2, 12.0 Hz, 1H), 2.86 – 2.77 (m, 1H), 2.74 – 2.63 (m, 2H), 2.60 – 2.50 (m, 2H), 2.02 – 1.94 (m, 1H), 1.74 – 1.64 (m, 1H), 1.62 – 1.42 (m, 2H).

於 表 6中之實例係使用與針對 實例 32之合成所述相似之方法來製備。 表 6 實例編號 結構 名稱 質量離子計算值 / 觀測值 33 第一步驟之起始材料係 中間物 6。 ( S)-7-(1,1-二氧代-1,2-噻嗪-2-基)-3-(2-(哌啶-3-基胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 520.17/520.59 34 7-(1,1-二氧代異四氫噻唑-2-基-3-(2-((( 3S,6S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 518.17/518.28 (neg) 35 第一步驟之起始材料係 中間物 6。 7 -(1,1-二氧代-1,2-噻嗪-2-基)-3-(2-((( 3S,6S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 532.18/532.36 (neg) 36 ( S)-3-(2-((6,6-二甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈 532.18/532.32 (neg) 37 第一步驟之起始材料係 中間物 6。 ( S)-3-(2-((6,6-二甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代-1,2-噻嗪-2-基)-1 H-吲哚-6-甲腈 546.20/546.33 (neg) 38 ( S)-3-(2-((5,5-二甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈 532.18/532.32 (neg) 39 第一步驟之起始材料係 中間物 6。 ( S)-3-(2-((5,5-二甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代-1,2-噻嗪-2-基)-1 H-吲哚-6-甲腈 548.20/548.88 40 7-(1,1-二氧代異四氫噻唑-2-基)-3-(2-(((1 S,2 S)-2(乙基胺基)環戊基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 532.18/532.32 (neg) 41 第一步驟之起始材料係 中間物 6。 7-(1,1-二氧代-1,2-噻嗪-2-基)-3-(2-(((1S,2S)-2-(乙基胺基)環戊基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-甲腈 548.20/548.64 實例 A The examples in Table 6 were prepared using methods similar to those described for the synthesis of Example 32 . Table 6 instance number structure name Mass ion calculated value / observed value 33 The starting material for the first step is intermediate 6 . ( S )-7-(1,1-dioxo-1,2-thiazin-2-yl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl )pyrimidin-4-yl) -1H -indole-6-carbonitrile 520.17/520.59 34 7-(1,1-dioxoisotetrahydrothiazol-2-yl-3-(2-((( 3S,6S )-6-methylpiperidin-3-yl)amino)-5-( Trifluoromethyl)pyrimidin-4-yl) -1H -indole-6-carbonitrile 518.17/518.28 (neg) 35 The starting material for the first step is intermediate 6 . 7-(1,1-dioxo-1,2-thiazin-2-yl)-3-(2-((( 3S,6S )-6-methylpiperidin-3-yl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carbonitrile 532.18/532.36 (neg) 36 ( S )-3-(2-((6,6-Dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1 -Dioxoisotetrahydrothiazol-2-yl)-1 H -indole-6-carbonitrile 532.18/532.32 (neg) 37 The starting material for the first step is intermediate 6 . ( S )-3-(2-((6,6-Dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1 -Dioxo-1,2-thiazin-2-yl)-1 H -indole-6-carbonitrile 546.20/546.33 (neg) 38 ( S )-3-(2-((5,5-Dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1 -Dioxoisotetrahydrothiazol-2-yl)-1 H -indole-6-carbonitrile 532.18/532.32 (neg) 39 The starting material for the first step is intermediate 6 . ( S )-3-(2-((5,5-Dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1 -Dioxo-1,2-thiazin-2-yl)-1 H -indole-6-carbonitrile 548.20/548.88 40 7-(1,1-dioxoisotetrahydrothiazol-2-yl)-3-(2-(((1 S ,2 S )-2(ethylamino)cyclopentyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carbonitrile 532.18/532.32 (neg) 41 The starting material for the first step is intermediate 6 . 7-(1,1-dioxo-1,2-thiazin-2-yl)-3-(2-(((1S,2S)-2-(ethylamino)cyclopentyl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-1 H -indole-6-carbonitrile 548.20/548.64 Example A

在Reaction Biology Corporation使用「HotSpot」檢定平台評估CDK7酶抑制活性，如文獻所公開(Anastassiadis T. et al., Nat Biotechnol. 2011, 29(11):1039-45)。資料提供於表7中。CDK7 enzyme inhibitory activity was assessed at Reaction Biology Corporation using the "HotSpot" assay platform as published (Anastassiadis T. et al., Nat Biotechnol. 2011, 29(11):1039-45). Data are provided in Table 7.

CDK7抑制劑抑制MCF7及OVCAR3細胞之生長的效果係經存活力檢定之6天-時間週期來評估（表7）。簡言之，將候選細胞系分別以以下細胞密度接種於96孔盤中，MCF7為3000至3500個細胞/孔，OVCAR-3為3000個細胞/孔。24小時後，用各種濃度之化合物（將化合物以1:3稀釋於DMSO中，10個點）來處理細胞。無化合物之DMSO溶劑作為對照。在37℃下、5% CO2培養箱中培養6天後，使用CellTiter-Glo螢光細胞存活力檢定(Promega, Cat# G7570)來分析細胞。所有存活力檢定均重複進行，且使用Envision (Perkin Elmer, USA)讀取螢光。使用非線性回歸、及S形劑量-反應曲線，用Graphpad Prism軟體來計算EC50。The effect of CDK7 inhibitors on growth inhibition of MCF7 and OVCAR3 cells was assessed over a 6 day-time period of viability assay (Table 7). Briefly, candidate cell lines were seeded in 96-well plates at the following cell densities, 3000 to 3500 cells/well for MCF7 and 3000 cells/well for OVCAR-3. After 24 hours, cells were treated with various concentrations of compound (compound diluted 1:3 in DMSO, 10 points). DMSO solvent without compound was used as a control. After 6 days of incubation at 37°C in a 5% CO2 incubator, the cells were analyzed using the CellTiter-Glo fluorescent cell viability assay (Promega, Cat# G7570). All viability assays were performed in duplicate and fluorescence was read using Envision (Perkin Elmer, USA). EC50s were calculated using nonlinear regression, and sigmoidal dose-response curves with Graphpad Prism software.

此等檢定之結果係顯示於表7中，其中「A」表示量測之CDK7/週期蛋白H IC 50小於10 nM、或OVCAR3 CGT EC 50小於100 nM、或MCF7 CGT EC 50小於100 nM；「B」表示量測之CDK7/週期蛋白H IC 50介於10 nM與小於100 nM之間、或OVCAR3 CGT EC 50介於100 nM與小於1 µΜ之間、或MCF7 CGT EC 50介於100 nM與小於1µm之間；「C」表示量測之CDK7/週期蛋白H IC 50大於或等於100 nM、或OVCAR3 CGT EC 50大於或等於1 µΜ、或MCF CGT EC 50大於或等於1 µΜ，且「NT」表示指定化合物在指定檢定中並未測試。 表 7 實例編號 CDK7/ 週期蛋白 H/IC 50(nM) OVCAR3 EC 50(nM) MCF7 EC 50(nM) 1 B A NT 2 B B NT 3 B A A 4 B A A 5 B B NT 6 B B NT 7 A A B 8 B B NT 9 B A NT 10 B A NT 11 A A B 12 B B NT 13 B C NT 14 A A NT 15 B A NT 17 B B NT 18 B C NT 19 B B NT 20 A C NT 21 A B NT 22 B B NT 23 B B NT 24 A B NT 25 B B NT 26 B B NT 27 A B NT 28 B C NT 29 A B NT 30 A B NT 31 B B NT The results of these assays are shown in Table 7, where "A" indicates a measured CDK7/cyclin H IC50 of less than 10 nM, or an OVCAR3 CGT EC50 of less than 100 nM, or an MCF7 CGT EC50 of less than 100 nM;" B” indicates that the measured CDK7/cyclin H IC 50 is between 10 nM and less than 100 nM, or the OVCAR3 CGT EC 50 is between 100 nM and less than 1 µM, or the MCF7 CGT EC 50 is between 100 nM and less than 1 µM; "C" indicates that the measured CDK7/cyclin H IC 50 is greater than or equal to 100 nM, or the OVCAR3 CGT EC 50 is greater than or equal to 1 µM, or the MCF CGT EC 50 is greater than or equal to 1 µM, and "NT ” indicates that the specified compound was not tested in the specified assay. Table 7 instance number CDK7/ Cyclin H/IC 50 (nM) OVCAR3 EC 50 (nM) MCF7 EC 50 (nM) 1 B A NT 2 B B NT 3 B A A 4 B A A 5 B B NT 6 B B NT 7 A A B 8 B B NT 9 B A NT 10 B A NT 11 A A B 12 B B NT 13 B C NT 14 A A NT 15 B A NT 17 B B NT 18 B C NT 19 B B NT 20 A C NT twenty one A B NT twenty two B B NT twenty three B B NT twenty four A B NT 25 B B NT 26 B B NT 27 A B NT 28 B C NT 29 A B NT 30 A B NT 31 B B NT

此外，雖然前述已藉由說明和示例之方式稍微詳細地描述以達清晰及理解之目的，所屬技術領域中具有通常知識者將理解可進行各式各樣的改良而不背離本揭露之精神。因此，應清楚理解在本文中揭示之形式僅用以說明，且並非意欲限制本揭露之範疇，而是亦涵蓋伴隨本揭露之真實範疇及精神而來的所有修改及替代方案。Furthermore, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that various modifications can be made without departing from the spirit of the disclosure. Therefore, it should be clearly understood that the forms disclosed herein are for illustration only, and are not intended to limit the scope of the disclosure, but also cover all modifications and alternatives accompanying the true scope and spirit of the disclosure.

〔圖1〕繪示用於製備式(I)化合物之通用合成方案。 〔圖2〕繪示用於製造7-溴-3-(2,5-二氯嘧啶-4-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1 H-吲哚-6-甲腈（中間物2）之反應方案。 〔圖3〕繪示用於製造3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(1,1-二氧代異四氫噻唑-2-基)-1 H-吲哚-6-甲腈（中間物5）之反應方案。 〔圖4〕繪示用於製造3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈（實例1）之反應方案。 〔圖5〕繪示用於製造3-(5-氯-2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)嘧啶-4-基)-7-(1-氧代磷烷-1-基)-1 H-吲哚-6-甲腈（實例8）之反應方案。 〔圖6〕繪示用於製造 N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吡咯并[2,3- b]吡啶-6-羧醯胺（實例18）之反應方案。 〔圖7〕繪示用於製造 N-(3,5-二甲基異 唑-4-基)-3-(2-(((3 S,6 S)-6-甲基哌啶-3-基)胺基)-5-(三氟甲基)嘧啶-4-基)-1 H-吲哚-6-羧醯胺（實例28）之反應方案。 [Fig. 1] shows a general synthetic scheme for the preparation of compounds of formula (I). 〔Figure 2〕Schematic diagram for the production of 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- Reaction scheme for 1 H -indole-6-carbonitrile (Intermediate 2). 〔Figure 3〕Schematic diagram for the production of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxoisotetrahydrothiazol-2-yl) - Reaction scheme for 1 H -indole-6-carbonitrile (Intermediate 5). 〔Figure 4〕Schematic diagram for the production of 3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4 Reaction scheme for -yl)-7-(1-oxophosphoran-1-yl) -1H -indole-6-carbonitrile (Example 1). 〔Figure 5〕Schematic diagram for the production of 3-(5-chloro-2-((( 3S , 6S )-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7 Reaction scheme for -(1-oxophosphoran-1-yl) -1H -indole-6-carbonitrile (Example 8). [Figure 6] shows the Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -pyrrolo[2,3- b ]pyridine-6-carboxamide (Example 18) reaction scheme. [Fig. 7] shows the Azol-4-yl)-3-(2-(((3 S ,6 S )-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) -1H -Indole-6-carboxamide (Example 28) reaction scheme.

Claims (58)

一種式(I)之化合物， (I) 或其醫藥上可接受之鹽，其中 R 1及R 2獨立地係氫、鹵素、CN、烷基、烷氧基、鹵烷基、羥烷基、環烷基、NHR 5a、或NR 5aR 5b； R 3係經取代或未經取代之C 3-C 8環烷基、或C 3-C 8雜環基，其中該經取代之C 3-C 8環烷基、或C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基、烷氧基、鹵烷基、環烷基、雜環基、NHR 5a、NR 5aR 5b、或OR 6之基團所取代； R 4係鹵素、CN、烷基、環烷基、-NR 7R 8、OR 6、-CO 2R 6、或-C(O)-NR 7R 8； 各R 5a、R 5b、及R 6獨立地係氫、烷基、鹵烷基、或環烷基； R 7及R 8獨立地係氫、經取代或未經取代之烷基、或經取代或未經取代之環烷基；其中該經取代之烷基或經取代之環烷基係經1至3個獨立地選自鹵素、OR 6、CN、烷基、NHR 5a、或NR 5aR 5b所取代；或 R 7及R 8連同其所連接之N一起形成未經取代或經取代的C 3-C 8雜環基，其中該經取代之C 3-C 8雜環基係經一或多個獨立地選自鹵素、烷基、烷氧基、鹵烷基、環烷基、雜環基、NHR 5a、NR 5aR 5b或OR 6之基團所取代； X係N或CR 9； Q 1係C或N； Q 2係CH或N； Q 3係CH、N、或NH；前提係當Q 1係N時，則Q 3係N； R 9係氫、 、 、或 ； 各R 10獨立地係氫、烷基、鹵烷基、或環烷基； Y及Z獨立地係N或CH，且 各n獨立地係0、1、2、3、或4。 A compound of formula (I), (I) or a pharmaceutically acceptable salt thereof, wherein R and R are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , or NR 5a R 5b ; R 3 is substituted or unsubstituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl, wherein the substituted C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocyclyl is one or more independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 Substituted by a group; R 4 is halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , -CO 2 R 6 , or -C(O)-NR 7 R 8 ; each R 5a , R 5b , and R 6 are independently hydrogen, alkyl, haloalkyl, or cycloalkyl; R 7 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted wherein the substituted alkyl or substituted cycloalkyl is substituted by 1 to 3 independently selected from halogen, OR 6 , CN, alkyl, NHR 5a , or NR 5a R 5b ; Or R 7 and R 8 together with the N to which they are attached form an unsubstituted or substituted C 3 -C 8 heterocyclyl, wherein the substituted C 3 -C 8 heterocyclyl is through one or more independent Substituted by a group selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b or OR 6 ; X is N or CR 9 ; Q 1 is C or N; Q 2 is CH or N; Q 3 is CH, N, or NH; the premise is that when Q 1 is N, then Q 3 is N; R 9 is hydrogen, , ,or each R 10 is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; Y and Z are independently N or CH, and each n is independently 0, 1, 2, 3, or 4. 如請求項1之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係氫。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is hydrogen. 如請求項1或2之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係鹵素。 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is halogen. 如請求項1至3中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係CN。 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is CN. 如請求項1至4中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係烷基。 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is an alkyl group. 如請求項1至5中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係烷氧基。 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is an alkoxy group. 如請求項1至6中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係鹵烷基。 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is haloalkyl. 如請求項1至7中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係環烷基。 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is cycloalkyl. 如請求項1至8中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係NHR 5a。 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is NHR 5a . 如請求項1至9中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係NR 5aR 5b。 The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is NR 5a R 5b . 如請求項1至10中任一項之化合物、或其醫藥上可接受之鹽，其中R 1及R 2中之至少一者係氫、氯基、氟基、甲基、羥乙基、或三氟甲基。 The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein at least one of R and R is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or Trifluoromethyl. 如請求項1至11中任一項之化合物、或其醫藥上可接受之鹽，其中R 3係經取代之C 3-C 8環烷基。 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3 is a substituted C 3 -C 8 cycloalkyl group. 如請求項1至11中任一項之化合物、或其醫藥上可接受之鹽，其中R 3係未經取代之C 3-C 8環烷基。 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3 is an unsubstituted C 3 -C 8 cycloalkyl group. 如請求項1至11中任一項之化合物、或其醫藥上可接受之鹽，其中R 3係經取代之C 3-C 8雜環基。 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3 is a substituted C 3 -C 8 heterocyclic group. 如請求項1至11中任一項之化合物、或其醫藥上可接受之鹽，其中R 3係未經取代之C 3-C 8雜環基。 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3 is an unsubstituted C 3 -C 8 heterocyclic group. 如請求項1至15中任一項之化合物、或其醫藥上可接受之鹽，其中R 3係哌啶基、甲基哌啶基、二甲基哌啶基、二氟基哌啶基、吡咯啶基、(N-乙基胺基)環丁基、(N-乙基胺基)環戊基、氮雜螺辛基、氮雜螺壬基、或氧雜氮雜螺癸基。 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R is piperidinyl , methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, Pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxazaspirodecyl. 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係鹵素。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen. 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係CN。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is CN. 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係烷基。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is an alkyl group. 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係環烷基。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is cycloalkyl. 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係-NR 7R 8。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is -NR 7 R 8 . 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係OR 6。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is OR 6 . 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係-CO 2R 6。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is -CO 2 R 6 . 如請求項1至16中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係-C(O)-NR 7R 8。 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(O)-NR 7 R 8 . 如請求項1至24中任一項之化合物、或其醫藥上可接受之鹽，其中R 4係CN、N,N-二甲基醯胺基、N,N-二乙基醯胺基、 、 、 、 、或 。 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof , wherein R is CN, N,N-dimethylamido, N,N-diethylamido, , , , ,or . 如請求項1至24中任一項之化合物、或其醫藥上可接受之鹽，其中R 5a、R 5b、及R 6中之至少一者係氫。 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a , R 5b , and R 6 is hydrogen. 如請求項1至24中任一項之化合物、或其醫藥上可接受之鹽，其中R 5a、R 5b、及R 6中之至少一者係烷基。 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a , R 5b , and R 6 is an alkyl group. 如請求項1至24中任一項之化合物、或其醫藥上可接受之鹽，其中R 5a、R 5b、及R 6中之至少一者係鹵烷基。 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a , R 5b , and R 6 is haloalkyl. 如請求項1至24中任一項之化合物、或其醫藥上可接受之鹽，其中R 5a、R 5b、及R 6中之至少一者係環烷基。 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a , R 5b , and R 6 is cycloalkyl. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者獨立地係氫、經取代或未經取代之烷基、或經取代或未經取代之環烷基。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R and R is independently hydrogen, substituted or unsubstituted alkyl, or Substituted or unsubstituted cycloalkyl. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者係氫。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R 7 and R 8 is hydrogen. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者係經取代之烷基。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R 7 and R 8 is a substituted alkyl group. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者係未經取代之烷基。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R 7 and R 8 is an unsubstituted alkyl group. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者係經取代之環烷基。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R 7 and R 8 is a substituted cycloalkyl group. 如請求項1至29中任一項之化合物、或其醫藥上可接受之鹽，其中R 7及R 8中之至少一者係未經取代之環烷基。 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R 7 and R 8 is unsubstituted cycloalkyl. 如請求項1至35中任一項之化合物、或其醫藥上可接受之鹽，其中X係N。The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is N. 如請求項1至35中任一項之化合物、或其醫藥上可接受之鹽，其中X係CR 9。 The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is CR 9 . 如請求項1至37中任一項之化合物、或其醫藥上可接受之鹽，其中Q 1係C。 The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q 1 is C. 如請求項1至37中任一項之化合物、或其醫藥上可接受之鹽，其中Q 1係N且Q 3係N。 The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q 1 is N and Q 3 is N. 如請求項1至39中任一項之化合物、或其醫藥上可接受之鹽，其中Q 2係CH。 The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CH. 如請求項1至39中任一項之化合物、或其醫藥上可接受之鹽，其中Q 2係N。 The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q 2 is N. 如請求項1至38、40或40中任一項之化合物、或其醫藥上可接受之鹽，其中Q 3係CH。 The compound according to any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CH. 如請求項1至40中任一項之化合物、或其醫藥上可接受之鹽，其中Q 3係N。 The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Q 3 is N. 如請求項1至38、40或40中任一項之化合物、或其醫藥上可接受之鹽，其中Q 3係NH。 The compound according to any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q 3 is NH. 如請求項1至44中任一項之化合物、或其醫藥上可接受之鹽，其中R 9係氫。 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen. 如請求項1至44中任一項之化合物、或其醫藥上可接受之鹽，其中R 9係 。 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R is . 如請求項1至44中任一項之化合物、或其醫藥上可接受之鹽，其中R 9係 。 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R is . 如請求項1至44中任一項之化合物、或其醫藥上可接受之鹽，其中R 9係 。 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R is . 如請求項1至48中任一項之化合物、或其醫藥上可接受之鹽，其中R 9係 、 、 、 、或 。 The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R is , , , ,or . 如請求項1至49中任一項之化合物、或其醫藥上可接受之鹽，其中Y及Z中之至少一者係N。The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is N. 如請求項1至49中任一項之化合物、或其醫藥上可接受之鹽，其中Y及Z中之至少一者係CH。The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is CH. 如請求項1至51中任一項之化合物、或其醫藥上可接受之鹽，其前提係當各R 10獨立地係甲基或乙基，式(I)不係 。 As the compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, the premise is that each R 10 is independently methyl or ethyl, and formula (I) is not . 如請求項1之化合物、或其醫藥上可接受之鹽，其中該化合物係選自係選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、或 。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or . 一種醫藥組成物，其包含如請求項1至53中任一項之化合物或其醫藥上之活性鹽、及醫藥上可接受之載體、稀釋劑、賦形劑、或其組合。A pharmaceutical composition, which comprises the compound according to any one of claims 1 to 53 or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. 一種用於治療癌症或腫瘤之方法，其包含向患有該癌症或該腫瘤之對象投予有效量之如請求項1至53中任一項之化合物、或其醫藥上之活性鹽、或如請求項54之醫藥組成物。A method for treating cancer or tumor, comprising administering an effective amount of a compound according to any one of claims 1 to 53, or a pharmaceutically active salt thereof, or such as The pharmaceutical composition of claim 54. 如請求項55之方法，其中該癌症或該腫瘤係選自泌尿上皮癌、子宮癌、結腸直腸癌、乳癌、肺癌、卵巢癌、胃癌、肝膽癌、胰臟癌、子宮頸癌、***癌、血液癌、肉瘤、皮膚癌、或神經膠質瘤。The method of claim 55, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, liver and gallbladder cancer, pancreatic cancer, cervical cancer, prostate cancer, Blood cancer, sarcoma, skin cancer, or glioma. 一種有效量之如請求項1至53中任一項之化合物、或其醫藥上之活性鹽、或如請求項54之醫藥組成物在製造用於治療癌症或腫瘤之藥劑中的用途。Use of an effective amount of a compound according to any one of claims 1 to 53, or a pharmaceutically active salt thereof, or a pharmaceutical composition according to claim 54 in the manufacture of a medicament for treating cancer or tumor. 如請求項57之用途，其中該癌症或該腫瘤係選自泌尿上皮癌、子宮癌、結腸直腸癌、乳癌、肺癌、卵巢癌、胃癌、肝膽癌、胰臟癌、子宮頸癌、***癌、血液癌、肉瘤、皮膚癌、或神經膠質瘤。As the purposes of claim 57, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, liver and gallbladder cancer, pancreatic cancer, cervical cancer, prostate cancer, Blood cancer, sarcoma, skin cancer, or glioma.
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